program 6th annual peptide therapeutics symposium · 2014-05-19 · roche’s personalised...

Program6th Annual Peptide

Therapeutics Symposium

October 20 – 21, 2011

Salk Institute for Biological Studies

La Jolla, CA

www.peptidetherapeutics.org

Table of Contents

6th Annual Peptide Therapeutics SymposiumContents

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Welcome ......... ..........................................................................................................................................3

Foundation Sponsors ..............................................................................................................................4 Amylin Pharmaceutical .................................................................................................................4 CovX .............................................................................................................................................4 Ferring Pharmaceuticals ...............................................................................................................5 Ipsen ...... .......................................................................................................................................5 The PolyPeptide Group .................................................................................................................6 Roche .... .......................................................................................................................................6 Zydus Cadila .................................................................................................................................7

Schedule of Events ..................................................................................................................................8

Speaker Biographies ..............................................................................................................................12

Abstracts of Lecture Presentations ......................................................................................................23 NPY2R Selective Peptide Agonists for the Treatment of Obesity: Balancing Efficacy,TimeActionandCardiovascularProfile JordiAlsina,Ph.D...........................................................................................................24

DevelopmentofaLong-actingC-peptide(Ersatta™) JamesCallaway,Ph.D....................................................................................................24

EPiC Technology: Using Peptide to Physiologically Cross the BBB JeanPaulCastaigne,M.D.,MBA...................................................................................24

DevelopmentofCR845,aNovel,Peripherally-ActingPeptidicKappaOpioid Agonist,fortheTreatmentofPostoperativePain DerekChalmers,Ph.D.,D.Sc.........................................................................................25

LongActingY2RPeptideMimeticasaNewGenerationTherapeutic AgentfortheManagementofT2D WaleedDanho,Ph.D......................................................................................................25

Somatostatin-DopamineChimericMoleculeforPotentialTreatmentof Pituitary Adenomas and Neuroendocrine Tumors JesseZ.Dong,Ph.D......................................................................................................26

ZYPH0907: A Novel Orally Active PTH1R Agonist for Treatment of Osteoporosis MukulJain,Ph.D............................................................................................................26

ComparativePeptidomicAnalysisforFunctionalDiscoveryofNeuropeptides LingjunLi,Ph.D..............................................................................................................27

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Symposium Sponsors

6th Annual Peptide Therapeutics SymposiumContents

TargetingProteinTherapeuticsAcrosstheBlood-BrainBarrierwith MolecularTrojanHorses WilliamM.Pardridge,Ph.D............................................................................................27

An Expanding Genetic Code PeterSchultz,Ph.D........................................................................................................27

Neuropeptidomics:FromtheDiscoveryofNewNeuropeptidestothe Elucidation of their Functions JonathanSweedler,Ph.D...............................................................................................28

HighResolutionMassSpectrometry-BasedProfilingofSecreted PeptidesforDrugDiscovery StevenTaylor,Ph.D........................................................................................................28

EndogenousPeptidestoSafelyEnhancetheDeliveryof(peptide) DrugstotheBrain WillemvanWerperen,MSc,MBA..................................................................................29

EnhancingCNSUptakeofBiologicsthroughMolecularEngineering RyanWatts,Ph.D...........................................................................................................29

Abstracts of Posters ..............................................................................................................................31

Table of Contents

Dear Colleagues,

Welcome to the 6th Annual Peptide Therapeutics Symposium. We aredelightedthatyouareabletojoinusforanotherstimulatingmeeting dedicated to the research and development of peptide therapeutics and technologies.

This year’s program highlights the transition from basic to applied science,fromdrugdiscoverytoclinicaldevelopmentfocusingonthemostpromisingadvanceswithinthepeptidefield.

The meeting begins with a session on Novel Peptide Therapeutics,followed by a panel discussion on What’s Driving R&D Today? We have expanded the program this year by introducing a Poster SessiontocoincidewiththeOpeningReception.Pleasetakethetimetobrowsethroughthepostersasyouenjoythecompanyofcolleagues and friends.

OnFridaymorning,theprogrambeginswithakeynoteaddressby Peter Schultz and a plenary lecture by William Pardridge addressing exciting new frontiers in peptide research. In the afternoon,lecturesanddiscussionsonthelatestadvancesinDiscovery Pharmacology; Peptide Transport; and Novel Peptide Therapeutics will conclude the program.

Enjoytheprogram,postersession,lectures,andtheopportunitytonetworkwithyourpeers.

Withkindregards,

RichardDiMarchiandPierreRivièreOn behalf of Peptide Therapeutics Foundation

Sponsors, Peptide Therapeutics Foundation Amylin PharmaceuticalsCovXFerring Research InstituteIpsenPolyPeptide GroupRocheZydus Cadila

6th Annual Peptide Therapeutics SymposiumWelcome

PhotocourtesyofthelaboratoryofPamelaItkin-Ansari,Ph.D.,AdjunctAssistant

Professor,Sanford-BurnhamMedicalResearchInstitute/UCSD,LaJolla,CA

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Foundation Sponsors 6th Annual Peptide Therapeutics Symposium

Amylin Pharmaceuticals

Amylin Pharmaceuticals is a biopharmaceutical company committed to improvinglivesthroughthediscovery,developmentandcommercializationof innovative medicines. Amylin has developed and gained approval for twofirst-in-classmedicinesfordiabetes,SYMLIN®(pramlintideacetate)injectionandBYETTA®(exenatide)injection.Amylin’sresearchanddevelopment activities leverage the Company’s expertise in metabolism to develop potential therapies to treat diabetes and obesity. Amylin is headquarteredinSanDiego,California.FurtherinformationaboutAmylinPharmaceuticals is available at www.amylin.com.

CovX

CovXSanDiegoisoneoftheBiotechResearchUnitswithinPfizerWorldwideResearch&Development.ThereareR&DsitesacrosstheUnitedStates,aswellasEuropeandAsia.CovXcontributestoPfizer’sbiotherapeutic portfolio by concentrating on the development of novel biotherapeuticconjugates,knownasCovX-Bodies.ThehighlyflexiblenatureofthetechnologyusedtoefficientlycreateCovX-BodiesalsoenablesCovXscientiststoidentifyhigh-valuebiologicaltargetsandtoexpeditiouslymovecandidatestopre-clinicaldevelopmentandclinicalevaluation.

CollaboratingwithotherPfizersites,CovXscientistscombineskillsinpeptidescreeningandoptimizationwithstate-of-the-artbioconjugationcapabilities to provide therapies tailor made for therapeutic areas such as oncology and metabolic disease. Continuing innovation on the part of the approximately85scientistsandstaffhasprovidedmultiplenewplatformsthatcanbefurtherexploitedspecificallyforbifunctional/multifunctionalcapability.SincebeingacquiredbyPfizerin2008,CovXhasprogressedseveralmoleculesintoclinicalphasesofdevelopmentincludingCVX-060,anantiangiogenesisagentforcancerintoPhaseIb/IItrials;CVX-096,adrug for the treatment of diabetes into Phase I; and a novel bifunctional for solidtumors(CVX-241)intoPhaseI.

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Ipsen

Ipsenisaglobalbiopharmaceuticalgroup,withsalesexceeding€1billionin2009.TheGrouphastotalworldwidestaffofmorethan4,400employees,close to 900 of which contribute to the discovery and development of innovative drugs for patient care. Ipsen’s development strategy is based onfastgrowingspecialtycaredrugsinoncology,endocrinology,neurologyandhematology,andonprimarycaredrugs.Thisstrategyissupportedbyanactivepolicyofpartnerships.Ipsen’sresearch&development(R&D)centers and its peptide and protein engineering platform provide the Group withastrongcompetitiveedge.In2009,R&Dexpendituretotaledcloseto€200million,representingnearly20%ofGroupsales.Ipsen’ssharesaretradedonsegmentAofEuronextParis(stockcode:IPN,ISINcode:FR0010259150).TheGroupispartoftheSBF120index.IpsenhasimplementedaSponsoredLevelIAmericanDepositaryReceipt(ADR)program,whichtradeontheover-the-countermarketintheUnitedStatesunderthesymbolIPSEY.FormoreinformationonIpsen,visitourwebsiteatwww.ipsen.com.

Ferring Pharmaceuticals

FerringPharmaceuticals(Ferring)isaresearch-driven,specialtybiopharmaceutical company focused on peptides and proteins therapeutics. Thecompanyidentifies,developsandmarketsinnovativeproductsintheareasofreproductivehealth,urology,gastroenterologyandendocrinology.ThecompanyheadquarteredinSaint-Prex(Switzerland),employsover3,700peopleworldwide,operatessubsidiariesinaround50countriesandmarketsitsproductsinmorethan70countries.Ferring’skeyproductsincludeMINIRIN/DDAVP,PENTASAandMENOPUR.Thecompany’sR&DcentersarelocatedinSaint-Prex(Switzerland),Copenhagen(Denmark),Mumbai(India),BeerTuvia(Israel),SanDiegoandParsippany(UnitedStates)andTokyo(Japan).

TheFerringResearchInstitute,Inc.(FRI)wasestablishedinSanDiegoin1996 as the company’s center of excellence for peptide research. Building upon the company’s long standing tradition in peptides and “medicines on thebody’sownterms”,FRIhasdevelopedauniqueexpertiseinmodifyingnaturally-occurringpeptide/hormonestodesignpeptidetherapeuticswithimprovedpharmacodynamics,pharmacokineticsandpharmaceuticalproperties. This has lead in recent years to the discovery of a number of innovativepeptidicnewchemicalentities(NCEs)nowatvariousstagesofdevelopment,eitherinhouseorexternally.Asaresult,Ferringtodayhasthe largest portfolio and pipeline of peptide therapeutics.

TolearnmoreaboutFerring,itsresearchprojectsoritsproductspleasevisitwww.ferring.comandhttp://ferring-research.com.

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The PolyPeptide Group

The PolyPeptide Group is a leading provider of custom and generic GMP-gradepeptidesforarangeofpharmaceuticalandbiotechnologyapplications.Withcorporaterootsthatbeganinthe1950s,theGroupwasformallylaunchedin1996.Today,itoperatesagrowinginternationalnetworkofpeptidemanufacturingfacilities.Itsworld-classchemistsandsupport personnel offer an unparalleled range of services for clients of everysizeandateverystageofproductdevelopment.Moreinformationabout the PolyPeptide Group is available at www.PolyPeptide.com.

The Poly Peptide Group is comprised of 6 manufacturing sites that are exclusively focused on the manufacture of active pharmaceutical ingredients(APIs)basedonpeptidesandrelatedsubstances.ThePolyPeptide Group is privately held and employs about 450+ staff worldwide.

ThePolyPeptideLaboratoriesGrouphasbeeninspectedbytheFDAandotherRegulatoryAuthoritiesnumeroustimes,includingmorethan15successfulFDAPAIinspections.Altogether,theGrouphasmorethan20approved APIs.

SincetheacquisitionofNeoMPS,theserviceofferingsofthePolyPeptideGrouphavegreatlyincreased.Wenowcanofferradio-labeledpeptides,cosmeticpeptides,generalorganicsyntheses,anextensivecatalogaswellassmallscaleGMPmanufacturinginadditiontoourlarge-scaleGMPmanufacturingservices.Ourcustomersrangefromemergingpharmaceutical companies and biotech organizations through to Big Pharma.Theremainingbusinessisprimarilylinkedtothesaleofpeptidegenerics,includingCalcitonin,Deslorelin,Gonadorelin,Goserelin,GRF(1-29)amide,Leuprolide,Octreotide,PTH(1-34),Somatostatin,TriptorelinandArg-Vasopressin,inadditiontoothers.

Roche

HeadquarteredinBasel,Switzerland,Rocheisaleaderinresearch-focused healthcare with combined strengths in pharmaceuticals and diagnostics. Roche is the world’s largest biotech company with truly differentiatedmedicinesinoncology,virology,inflammation,metabolismandCNS.Rocheisalsotheworldleaderinin-vitrodiagnostics,tissue-based cancer diagnostics and a pioneer in diabetes management. Roche’s personalised healthcare strategy aims at providing medicines and diagnostictoolsthatenabletangibleimprovementsinthehealth,qualityoflifeandsurvivalofpatients.In2010,Rochehadover80’000employeesworldwideandinvestedover9billionSwissfrancsinR&D.TheGrouppostedsalesof47.5billionSwissfrancs.Genentech,UnitedStates,isawhollyownedmemberoftheRocheGroup.RochehasamajoritystakeinChugaiPharmaceutical,Japan.Formoreinformation:www.roche.com.

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Zydus Cadila

Zydus Cadila is an innovative global pharmaceutical company that discovers,develops,manufacturesandmarketsabroadrangeof healthcare products. The group’s operations range from API to formulations,animalhealthproductsandcosmeceuticals.HeadquarteredinthecityofAhmedabadinIndia,thegrouphasglobaloperationsinfourcontinentsspreadacrossUSA,Europe,Japan,Brazil,SouthAfricaand25otheremergingmarkets.

Initsmissiontocreatehealthiercommunitiesglobally,ZydusCadiladelivers wide ranging healthcare solutions and value to its customers. Withover13,000employeesworldwide,aworld-classresearchanddevelopmentcentrededicatedtodiscoveryresearchandeightstate-of-the-artmanufacturingplants,thegroupisdedicatedtoimprovingpeople’slives.Recently,ZydusCadilawasdeclaredasthe‘EmergingCompanyof the Year’ by the Economic Times for Corporate Excellence in 2010. In keepingwithitsvision,thegroupachievedthebilliondollarmarkinsalesinMarch2011.Itisnowsettoemergeasoneoftheleadingglobalhealthcarecompanies with sales of over $3 billion by 2015 and a global research driven company by 2020.

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Schedule of Events 6th Annual Peptide Therapeutics Symposium

Schedule of Events

Thursday, October 20th

2:30 p.m. – 7:00 p.m. Registration Check-in FredericdeHoffmannAuditoriumReceptionArea,LowerLevel

3:15 p.m. – 6:00 p.m. 6th Annual Peptide Therapeutics Symposium Frederic de Hoffmann Auditorium

3:15 p.m. – 3:30 p.m. Welcoming Remarks SoumitraGhosh,Ph.D. Director, Peptide Therapeutics Foundation Senior Director, Research, Amylin Pharmaceuticals

3:30 p.m. – 4:45 p.m. Opening Session: Novel Peptide Therapeutics 1

OpeningSessionModerator SoumitraGhosh,Ph.D. Director, Peptide Therapeutics Foundation Senior Director, Research, Amylin Pharmaceuticals

3:30 p.m. – 3:55 p.m. Development of a Long-acting C-peptide (Ersatta™) JamesCallaway,Ph.D. President and CEO, Cebix Incorporated

3:55 p.m. – 4:20 p.m. Long Acting Y2R Peptide Mimetic as a New Generation Therapeutic Agent for the Management of T2D WaleedDanho,Ph.D. Distinguished Research Leader, Hoffmann-La Roche Inc.

4:20 p.m. – 4:45 p.m. Somatostatin-Dopamine Chimeric Molecule for Potential Treatment of Pituitary Adenomas and Neuroendocrine Tumors JesseZ.Dong,Ph.D. Director, Peptide Therapeutics Foundation Vice President, Compound Discovery, Ipsen

4:45 p.m. – 6:00 p.m. Panel Discussion: What’s driving R&D funding today?

Panel Introductions MichelPettigrew,MBA President of the Executive Board & Chief Operating Officer, Ferring Pharmaceuticals

PanelModerator RichardDiMarchi,Ph.D. Symposium Chair & Chairman of the Board, Peptide Therapeutics Foundation Cox Professor of Biochemistry & Gill Chair in Biomolecular Sciences Department of Chemistry, Indiana University Panelists Hans-JoachimBöhm,Ph.D. Director, Peptide Therapeutics Foundation Global Head of Chemistry, Roche; Center Manager, Roche Pharma Research & Early Development Site Basel

PhotocourtesyofthelaboratoryofInderVerma,Ph.D.,ProfessorIrwinandJoanJacobsChair

inExemplaryLifeScienceLaboratoryofGenetics,TheSalkInstituteforBiologicalStudies,LaJolla,CA

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Schedule of Events

Friday, October 21st

7:30 a.m. – 6:30 p.m. 6th Annual Peptide Therapeutics Symposium Frederic de Hoffmann Auditorium

7:30 a.m. – 12:00 p.m. Registration Check-in FredericdeHoffmannAuditoriumReceptionArea,LowerLevel

7:30a.m.–8:30a.m. Breakfast & Poster Viewing FredericdeHoffmannAuditoriumReceptionArea,LowerLevel

8:30a.m.–8:45a.m. Opening Remarks RodneyLappe,Ph.D. Director, Peptide Therapeutics Foundation Group Sr. Vice President, Pfizer Worldwide Research & Development; Chief Scientific Officer, CovX Research

8:45a.m.–9:30a.m. Keynote Address

An Expanding Genetic Code PeterSchultz,Ph.D. Scripps Family Chair Professor; Department of Chemistry, The Scripps Research Institute

9:30 a.m. –10:15 a.m. Plenary Lecture

Targeting Protein Therapeutics Across the Blood-Brain Barrier with Molecular Trojan Horses WilliamM.Pardridge,Ph.D. Distinguished Professor of Medicine, University of California, Los Angeles

10:15 a.m. – 10:45 a.m. Beverage Break & Poster Viewing FredericdeHoffmannAuditoriumReceptionArea,LowerLevel

6th Annual Peptide Therapeutics Symposium

Schedule of Events

Thursday, October 20th, continued StanCrooke,M.D.,Ph.D. Chairman of the Board and CEO, Isis Pharmaceutical, Inc. RodneyLappe,Ph.D. Director, Peptide Therapeutics Foundation Group Sr. Vice President, Pfizer Worldwide Research & Development; Chief Scientific Officer, CovX Research MichelPettigrew,MBA President of the Executive Board & Chief Operating Officer, Ferring Pharmaceuticals

6:00p.m.–8:00p.m. Opening Reception & Poster Session FredericdeHoffmannAuditoriumReceptionArea,LowerLevel

Schedule of EventsFriday, October 21st, continued 10:45 a.m. – 12:00 p.m. Session 1: Discovery Pharmacology

Session1Moderators BinuPhilip,MSc,MBA Business Development, Zydus Cadilla JeanE.F.Rivier,Ph.D. Frederik Paulsen Chair in Neurosciences, Clayton Foundation Laboratory of Peptide Biology, Salk Institute for Biological Studies

10:45 a.m. – 11:10 a.m. Neuropeptidomics: From the Discovery of New Neuropeptides to the Elucidation of their Functions JonathanSweedler,Ph.D. Professor of Chemistry, James R. Eiszner Family Chair, University of Illinois, Urbana-Champaign

11:10 a.m. – 11:35 a.m. Comparative Peptidomic Analysis for Functional Discovery of Neuropeptides LingjunLi,Ph.D. Professor, School of Pharmacy and Department of Chemistry, University of Wisconsin

11:35 a.m. – 12:00 p.m. High Resolution Mass Spectrometry-Based Profiling of Secreted Peptides for Drug Discovery StevenTaylor,Ph.D. Director of Chemistry, Amylin Pharmaceuticals; Research Associate, Scripps Institution of Oceanography

12:00 p.m. – 1:30 p.m. Lunch & Poster Viewing FredericdeHoffmannAuditoriumReceptionArea,LowerLevel

1:30 p.m. – 3:15 p.m. Session 2: Peptide Transport

Session2Moderators JaneSalik,Ph.D. Director, Peptide Therapeutics Foundation CEO, PolyPeptide Group

ClaudioSchteingart,Ph.D. Vice President, Science & Technology, Ferring Research Institute

1:30 p.m. – 2:05 p.m. EPiC Technology: Using Peptide to Physiologically Cross the BBB JeanPaulCastaigne,M.D.,MBA President and CEO, AngioChem

2:05 p.m. – 2:40 p.m. Endogenous Peptides to Safely Enhance the Delivery of (peptide) Drugs to the Brain WillemvanWerperen,MSc,MBA CEO, to-BBB


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Schedule of Events

Friday, October 21st, continued 2:40 p.m. – 3:15 p.m. Enhancing CNS Uptake of Biologics through Molecular Engineering RyanWatts,Ph.D. Associate Director, Head of Neurodegeneration Labs, Department of Neuroscience, Genentech, Inc.

3:15 p.m. – 3:45 p.m. Beverage Break & Poster Viewing FredericdeHoffmannAuditoriumReceptionArea,LowerLevel

3:45 p.m. – 5:00 p.m. Session 3: Novel Peptide Therapeutics II

Session3Moderators JaniceReichert,Ph.D. Director, Peptide Therapeutics Foundation Senior Research Fellow, Tufts Center for the Study of Drug Development LesMiranda,Ph.D. Director Research, Peptide Research & Discovery, Chemistry Research & Discovery, Amgen

3:45 p.m. – 4:10 p.m. NPY2R Selective Peptide Agonists for the Treatment of Obesity: Balancing Efficacy, Time Action and Cardiovascular Profile JordiAlsina,Ph.D. Senior Research Scientist, Eli Lilly & Company

4:10 p.m. – 4:35 p.m. Development Of CR845, a Novel, Peripherally-Acting Peptidic Kappa Opioid Agonist, for the Treatment of Postoperative Pain DerekChalmers,Ph.D.,D.Sc. President & CEO, Cara Therapeutics, Inc.

4:35 p.m. – 5:00 p.m. ZYPH0907: A Novel Orally Active PTH1R Agonist for Treatment of Osteoporosis MukulJain,Ph.D. Senior Vice President, Zydus Research Center 5:00 p.m. – 5:15 p.m. Closing Remarks PierreRivière,Ph.D. President & Director, Peptide Therapeutics Foundation President, Ferring Research Institute & Senior Vice President, Research

5:15 p.m. – 6:30 p.m. Networking Reception FredericdeHoffmannAuditoriumReceptionArea,LowerLevel


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Speaker Biographies 6th Annual Peptide Therapeutics Symposium

Jordi Alsina, Ph.D. | Senior Research Scientist, Eli Lilly & CompanyNPY2R Selective Peptide Agonists for the Treatment of Obesity: Balancing Efficacy, Time Action and Cardiovascular Profile

Dr.AlsinagraduatedinChemistryfromtheUniversitatdeBarcelona,Spain.Hereceivedhis doctorate in Organic Chemistry from the same institution in 1997 under the supervision ofProf.FernandoAlbericioworkingonthedevelopmentofnewmethodsforthesolid-phasesynthesisofC-terminalmodifiedpeptidesincludingBackboneAmideLinker(BAL)Strategies.HecompletedpostdoctoraltraininginpeptidechemistrywithProf.GeorgeBaranyattheUniversityofMinnesotain2000,followedbythreeyearsatIndianaUniversity-PurdueUniversityatIndianapolisfocusingonthedevelopmentofsolid-phaseorganicchemistrymethodology.HejoinedLillyResearchLaboratoriesin2004asSeniorPeptideChemistandwaspromotedtoSeniorResearchScientistin2007.DuringhistimeatLillyResearchLaboratories,Dr.Alsinahasimpactedseveralimportantprogramsinthe diabetes and obesity therapeutic areas. He has gained recognition for the exploration andrefinementofpeptidestructure-activityrelationshipsandhispeptidesynthesisskills.Dr.Alsinahascontributedtothescientificcommunitywithmorethan40articlesininternationallyrecognizedpeer-reviewedjournalsinthesolid-phasepeptidechemistryandpeptide therapeutics areas.

Hans-Joachim Böhm, Ph.D. | Director, Peptide Therapeutics Foundation; Global Head of Chemistry, Roche; Center Manager, Roche Pharma Research & Early Development Site BaselPanelist

Hans-JoachimBöhmisGlobalHeadofChemistryatRocheandCenterManagerfortheRochePharmaResearchandEarlyDevelopmentSiteBasel.Priortothis,Hans-JoachimBöhmwasPresidentandResearchSiteHeadofRochePaloAltofromOctober2006toJune2008.Hans-JoachimBöhmalsoheadedNon-clinicaldevelopmentatRocheBaselfromJanuary2005untilSeptember2006,theDiscoveryChemistryDepartmentfrom2002–2004,theDiscoveryTechnologyDepartmentfrom2000-2001andtheResearchInformaticsDepartmentinBasel.BeforejoiningRochein1996,Hans-JoachimBöhmworkedforBASFinLudwigshafenasComputationalChemistfrom1988–1996andforSiemensinMunichinfieldofMicroelectronicsfrom1985-1987.HeobtainedhisPh.D.inTheoreticalChemistryattheUniversityofKarlsruhein1984.

James Callaway Ph.D. | President and CEO, Cebix IncorporatedDevelopment of a Long-acting C-peptide (Ersatta™)

Dr.JamesCallawayreceivedhisPh.D.inBiologicalChemistryatUCLAandsubsequentlyaccumulated over 25 years of experience in the development of biopharmaceutical productsatcompaniessuchasIngene(nowXoma),SmithKlineBeecham(nowGSK),Bayer,andElan.AtElanheservedinseveralcapacitiesincludingHeadofDevelopmentand was intimately involved in the advancement and approval of Tysabri®andMyobloc®. In addition,heservedastheleadaccountablepersoninthedesign,construction,validation,andFDAapprovalofabiologicsmanufacturingplant.

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Jean Paul Castaigne, M.D., MBA | President and CEO, AngioChemEPiC Technology: Using Peptide to Physiologically Cross the BBB

Dr.Castaigneisaseniorexecutivewithextensiveinternationalexperienceinthepharmaceuticalandbiotechindustry.PriortojoiningAngioChemasCEO,hewasCOOandCSOofConjuchem,andpreviouslyhewasVicePresident,HeadofGlobalR&DattheFournierGroupinFrance.Inaddition,Dr.CastaignespentelevenyearswithNovartisinavarietyofmanagementpositions,includingCorporateVicePresidentforCanada,PresidentandManagingDirectorinthePhilippinesandDirectorofMedicalandR&DinFrance.Dr.CastaignehasalsoworkedwithCILAG(J&J)andSanofiinFrance.HereceivedhisMDfrom Paris University in 1975 and held the position of Associate Professor of oncology andpneumologyin1978.Dr.CastaignereceivedanMBAfromHECParisin1987.Dr.Castaigne is member of the board of the following biotech companies: Tranzyme Pharma and Asmacure.

Derek Chalmers, Ph.D., D.Sc. | President & CEO, Cara Therapeutics, Inc.Development of CR845, a Novel, Peripherally-Acting Peptidic Kappa Opioid Agonist, for the Treatment of Postoperative Pain

Dr.ChalmershasbeentheCo-Founder,PresidentandCEOandExecutiveDirector,CaraTherapeuticssince2004,aClinical-stage,biotechnologycompanyfocusedondiscoveringanddevelopingnovel,superiortherapeuticstotreatpainandinflammation.Leadkappaagonist in Phase II studies.

Additionally,from1997-2004Dr.ChalmerswastheCo-Founder,VicePresidentandExecutiveDirectorofArenaPharmaceuticals(NASDAQ:ARNA),aPubliclytradedbiopharmaceutical company developing a broad pipeline of compounds that act on G protein-coupledreceptors,orGPCRs.Thecompanycurrentlyhastwodrugcandidatesinclinicaldevelopment.From1994-1997hewasthePrincipalInvestigatoratNeurocrineBiosciences(NASDAQ:NBIX),apubliclytradedproduct-basedbiopharmaceuticalcompanyfocusedonneurologicalandendocrinediseasesanddisorders.Andfrom1990-1994hewasaResearchFellow/NARSADFellow/FogertyInternationalFellowattheUniversityofMichigan.

Dr.ChalmersreceivedhisPh.D.fromtheUniversityofGlasgow,FacultyofMedicinein1990andhisB.Sc.(Hons)–UniversityofGlasgow,FacultyofSciencein1986.

Stan Crooke, M.D., Ph.D. | Chairman of the Board and CEO, Isis Pharmaceutical, Inc.Panelist

Dr.CrookeisFounder,ChairmanandChiefExecutiveOfficerofIsisPharmaceuticals.Isisis a development stage biopharmaceutical company that is focused on a new paradigm in drugdiscovery,antisenseoligonucleotides.SinceDr.CrookeandhiscolleaguesfoundedIsisin1989.TheCompanyhascompleteditsinitialpublicofferinginMay1991,andhasreported broad progress in antisense technology and its rapid conversion to therapeutic productopportunities.Isiswasthefirstcompanytocommercializeanantisensedrugandhasachievedanumberofimportantcorporatecollaborativerelationships.In2006,Dr.CrookewasnamedinNatureBiotechnologyasoneofbiotechnology’sinfluentialindividuals.

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PriortofoundingIsis,Dr.CrookewasPresidentofResearchandDevelopmentforSmithKlineBeckmanCorporation(SKB).HealsocoordinatedtheresearchanddevelopmentactivitiesofSKBincludingitsinstruments,diagnostics,animalhealthandclinicallaboratorybusinesses.PriortojoiningSKB,Dr.CrookehelpedestablishtheanticancerdrugdiscoveryanddevelopmentprogramatBristolMyers,whichsucceededinbringingtomarketasignificantnumberofdrugs.

Duringhiscareer,Dr.Crookehassupervisedthedevelopmentof19drugscurrentlyonthemarketandothersindevelopment.Dr.CrookehaswonanumberofteachingawardsandhasbeenaprofessorofpharmacologyatBaylorMedicalSchoolandtheUniversityofPennsylvania. He has trained a number of graduate students and numerous post doctoral fellows.Hehasauthoredover400publications,hasedited21books,andhasbeengrantedmanypatents.Dr.Crookeisactiveinmolecularandcellularbiologyandpharmacologyofantisenseoligonucleotides.DrCrookehasservedonnumerousboardsofdirectorsandvariouseditorialboards,andhaswonanumberofawards.

Dr.CrookereceivedhisM.D.andPh.D.fromBaylorCollegeofMedicine,Houston,TexasandhisB.S.inPharmacyfromButlerUniversity,Indianapolis,Indiana.

Waleed Danho, Ph.D. | Distinguished Research Leader, Hoffmann-La Roche Inc.Long Acting Y2R Peptide Mimetic as a New Generation Therapeutic Agent for the Management of T2D

Dr.WaleedDanhoholdsthepositionofDistinguishedResearchLeaderatHoffmann-LaRocheInc.inNutley,NewJersey,USA.(tillApril12011).Dr.DanhocompletedhisPh.D.in1967attheUniversityofAachen,Aachen,GermanyinthelaboratoriesofProfessorDr.mult.HelmutZahn.HewentontodopostdoctoraltrainingattheHormoneResearchLaboratory,UniversityofCalifornia,SanFranciscointhelaboratoriesofProfessorDr.ChohHaoLi.Hisresearchinterestsareindrugdiscoveryofpeptide-baseddrugs,peptidemimetics,andconformationallyrestrictedpeptides.

Dr.DanhoalsoservesasanadjunctprofessorattheUniversityofMedicineandDentistryofNewJersey,DepartmentofBiochemistry(1996-Present).HeisreviewerfortheJournal of Peptide Research,QSAR & Combinatorial Science,aswellasfortheJournal of Medicinal Chemistry; he is a member of the editorial board of The International Journal ofPeptideResearchandTherapeutics.Dr.Danhoauthoredandco-authoredover250scientificarticlesand21patentsinthefieldofpeptides.HehaspresentedandchairedvarioussectionsoftheAmerican,EuropeanandInternationalPeptideSymposiasince1972.HeisthewinneroftheWilhelmBorchesMedal(1968)ofTheUniversityofAachenforSummacuminthePhDProgram.In2009Dr.Danhowasawardedthe“LifetimeAchievement Award” from the North Jersey section of the American Chemical Society.

LastSeptember,Dr.Danhowasawardedthe“2009MeienhoferAward”atRocheColoradoCorporation Peptide Symposium “RCCPS 09.”

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Richard DiMarchi, Ph.D. | Symposium Chair & Chairman of the Board, Peptide Therapeutics Foundation; Cox Professor of Biochemistry & Gill Chair in Biomolecular Sciences; Department of Chemistry, Indiana UniversityPanel Moderator

Dr.DiMarchicontributionsinpeptide&proteinsciencesconsistsofthreedecadesofworkinacademia,thepharmaceuticalindustryandbiotechnologycompanies.HeistheCoxProfessor of Biochemistry and Gill Chair in Biomolecular Sciences at Indiana University. His current research is focused on developing macromolecules with enhanced therapeutic propertiesthroughbiochemicaloptimizationwithnon-naturalaminoacids,anapproachtermedchemical-biotechnology.Heisaco-founderofAmbrx,Inc.andMarcadiaBiotech.HeisascientificadvisortoFerring,Merck,Rocheandthreeventurefunds;5AM,TMP,andTwilight.

Dr.DiMarchiisaretiredGroupVicePresidentatEliLilly&Companywhereformorethantwodecadesheprovidedleadershipinbiotechnology,endocrineresearchandproductdevelopment.HeisreadilyrecognizedfordiscoveryanddevelopmentofrDNAderivedHumalog®(LisPro-humaninsulin).ThisdesignerinsulinrepresentsthefirstdemonstrationthatstructurallyalteredrDNA-derivedbiosyntheticproteinscanimprovepharmacologicalperformancewithoutincreasingtheriskofanabnormalimmunologicalresponse.Asscientistandmanager,Dr.DiMarchialsosignificantlycontributedtothecommercialdevelopment of Humulin®,Humatrope®,Xigris®,rGlucagon®,Evista®,andForteo®.

Dr.DiMarchiistherecipientofnumerousawardsincludingthe2005AAPSCareerResearchAchievementAwardinBiotechnology,the2006ACSBarnesAwardforLeadershipinChemicalResearchManagement,the2006ACSEsselenAwardforChemistryintheServiceofPublicInterest,the2007CarothersAwardforExcellenceinPolymerSciences,the2009WatanabeAwardforLifeSciencesResearch,andthe2011MerrifieldAwardforCareerContributionsinPeptideSciences.

Jesse Z. Dong, Ph.D. | Director, Peptide Therapeutics Foundation; Vice President, Compound Discovery, IpsenSomatostatin-Dopamine Chimeric Molecule for Potential Treatment of Pituitary Adenomas and Neuroendocrine Tumors

Dr.DonghasservedasVicePresidentofCompoundDiscoveryatIpsensince2009overseeingpeptideandtoxindrugdiscoveryresearch.HejoinedIpsen/Biomeasure,Incorporated in 1993 as a scientist in the medicinal chemistry department. He is the inventor of four drug candidates that are currently in development: Taspoglutide in phase IIIclinicaltrialsfortreatmentoftypeIIdiabetes,BA058inphaseIIIclinicaldevelopmentfortreatmentofpostmenopausalosteoporosis,RM-131inphaseIclinicaltrialforGIdisorders,andRM-493inpreclinicalstagefortreatmentofobesity.Duringhisdistinguishedscientificcareertodate,hehaspublishedover130scientificarticlesandhasbeenawarded27U.S.patents.PriortojoiningIpsen/Biomeasure,Dr.DongwasaResearchFellowintheUnitforRationalDrugDesign,DepartmentofMedicine,BostonUniversityMedicalCenter.HeholdsaPh.D.inOrganicChemistryfromOhioUniversity,Athens,OhioandM.S.andB.S.degreesfromPekingUniversity,Beijing,China.


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Soumitra Ghosh, Ph.D. | Director, Peptide Therapeutics Foundation; Senior Director, Research, Amylin Pharmaceuticals Welcoming Remarks

SoumitraGhoshisSeniorDirector,ResearchatAmylinPharmaceuticals,Inc.andjoinedthe company in 2003. He oversees the chemistry and biology research groups and leads a jointclinicaldevelopmentprogramofadiabetesdrugcandidatewithBiocon,India.PriortoAmylin,Dr.GhoshwasSeniorDirectorofChemicalBiologyatMitokorfortenyears,wherehedirecteditsdrugdiscoveryprogramsforCNSdisorders,osteoarthritisandobesity.HisworkexperiencealsoincludesdevelopmentofDNA-baseddiagnostictoolsandpeptidaseinhibitorsatBaxterDiagnostics,Inc.andattheSalkInstituteBiotechnology/IndustrialsAssociates(SIBIA).Dr.GhoshreceivedhisundergraduatetrainingatSt.Stephen’sCollege,Delhi,andobtainedhisM.S.andPh.D.degreesinChemistryfromtheIndianInstituteofTechnology,KanpurandtheUniversityofChicago,respectively.Heconductedhispost-doctoralresearchattheRockefellerUniversityinNewYork.

Mukul Jain, Ph.D. | Senior Vice President, Zydus Research CenterZYPH0907: A Novel Orally Active PTH1R Agonist for Treatment of Osteoporosis

Dr.MukulJainisleadingtheNewChemicalEntities(NCE)programatZydusResearchCentre(ZRC),theR&DwingofZydusCadilaGroup.Dr.JainobtainedhisB.Pharm.,M.Pharm.andPh.D.degreesplusadiplomainBusinessManagementfromNagpurUniversity,Nagpur,India.HealsohasacertificateinExecutiveManagementProgramfromIIM-Ahmedabad.AftercompletinghisPh.D.,heworkedasResearchScientistatWockhardtResearchCentre,AurangabadandthenatRanbaxyResearchLaboratoriesatNewDelhibeforemovingtoUSAasPost-docAssociateatUniversityofFloridaatGainesville.AfterspendingthreeyearsasaPost-docintheareaofMolecularNeuroendocrinology,hereturnedtoIndia&joinedNIPERasAssistantProfessorofPharmacology.

Intheyear2000,Dr.JainjoinedZRC,whenthisCentrehadjuststarteditsNCEResearchProgram and since then he has been associated with ZRC in various capacities. His groupatZRChasdeveloped11INDmolecules,including3peptidomimeticagentsthatare currently at different stages of clinical development. His group has also developed preclinicaldossierfor8recombinanttherapeuticproteinsandtheH1N1vaccinedevelopedby Zydus Cadila. Currently about 15 different NCE discovery programs are ongoing at ZRC. Underhissupervision,ZRChasreceivedvariousaccreditationsincludingOECD-GLP,NABL&AAALAC.Dr.Jainhascontributedtomorethan30patentsasco-inventorandmorethan130researchpublications,including68full-lengthresearchpapersinInternationalPeer-reviewedJournals.Dr.JainisconnectedwithvariousacademicinstitutesandhasguidedresearchworkofseveralMasters&Ph.Dstudents.HeisaFellowofAcademyofScience&AnimalWelfare,IndiaandtheChairmanoftheInstitutionalAnimalEthicsCommittee at ZRC.

HeisalsoamemberofseveralInternationalScientificCommunitiesincludingAmericanChemicalSociety,AmericanDiabetesAssociation,EuropeanAssociationforStudyofDiabetics,IndianPharmacologySociety,AmericanAssociationforAdvancementofSciences,InternationalBrainResearchOrganizationandWho’sWhoofProfessionalsetc.


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Rodney Lappe, Ph.D. | Director, Peptide Therapeutics Foundation; Group Sr. Vice President, Pfizer Worldwide Research & Development; Chief Scientific Officer, CovX ResearchPanelist & Opening Remarks

Dr.LappeisGroupSr.VicePresident,PfizerWorldwideResearchandDevelopmentandChiefScientificOfficerforCovXinSanDiego,California.Dr.LappejoinedPfizerwiththeCovXacquisitionin2008,bringing29yearsofdrugdiscoveryexperienceinthepharmaceutical and biotech industries.

Dr.Lappehasbeenresponsiblefortheadvancementofproteinbio-conjugatesthroughtheindustryleadingworkatCovX.Threenovelconjugates(CovX-bodies)addressingkeymedical needs in cancer and diabetes are now in clinical testing with two additional clinical candidatesinlatestagepreclinicaldevelopment.InadditiontoleadingCovX,Dr.LappehasrecentlytakenonresponsibilityforthecontinuedgrowthandproductivityofPfizer’sotherinternal Biotech Units as well.

PriortojoiningCovXasitsfirstCSOin2004,Dr.LappeservedasVicePresidentfor cardiovascular and metabolic diseases at Pharmacia where he contributed to the registration of Inspra®,anovelaldosteronereceptorantagonist.HewasalsositeleaderforPharmaciainSt.Louis.PriortojoiningPharmacia,heheldpositionsofincreasingresponsibilitywithWyeth,RorerCentralResearch,CIBAGeigyandSearlePharmaceuticals.

Dr.LappereceivedhisPh.D.inPharmacologyfromIndianaUniversityandhisBAfromBlackburnCollege.

Lingjun Li, Ph.D. | Professor, School of Pharmacy and Department of Chemistry, University of WisconsinComparative Peptidomic Analysis for Functional Discovery of Neuropeptides

ProfessorLingjunLireceivedherB.E.degreeinEnvironmentalAnalyticalChemistryfromBeijingUniversityofTechnologyandPh.D.degreeinAnalyticalChemistry/BiomolecularChemistryfromUniversityofIllinoisatUrbana-Champaignin2000.Shethendidathree-waypostdoctoralresearchatthePacificNorthwestNationalLaboratory,BrandeisUniversity,andUniversityofIllinoisbeforestartinghertenure-trackassistantprofessorpositioninDecember2002.Dr.LiwasrecruitedtoUW-Madisoncampusthroughacampus-wide“ChemicalBiologyClusterHire”positionandshecurrentlyholdsjointfacultyappointmentsinSchoolofPharmacyandDepartmentofChemistry.ShewaspromotedtoAssociateProfessorwithtenurein2008.Herresearchinterestsareinanalyticalneurochemistry,neuropeptidomicsandbiologicalmassspectrometry.Dr.Li’sresearchprogramfocusesondevelopingnovelmassspectrometrytoolsinconjunctionwith microseparation techniques to study challenging neuroscience problems including thefunctionaldiscoveryofneuropeptidesandbiomarkerdiscoveryinneurodegenerativediseases.Dr.Lihasestablishedahighlyproductiveresearchprogramandpublishedover100peer-reviewedresearchpapers,including80researchpaperssinceherindependentpositionatUW-Madison.Shehasobtainedmorethan$9Mresearchfundingandservedasrevieweronmorethan60scholarlyjournalsandnumerousfederalgrantreviewpanels.Shehas received numerous awards including a highly prestigious National Science Foundation CAREERAward,AlfredP.SloanFoundationResearchFellowship,VilasAssociateAward,theAmericanSocietyforMassSpectrometryResearchAward,theRomnesFacultyFellowship,and2011PittsburghConferenceAchievementAwardwithaspecialAwardSymposiumrecognizingandhonoringheroutstandingworkinBioanalyticalChemistry.


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William M. Pardridge, Ph.D. | Distinguished Professor of Medicine, University of California, Los AngelesTargeting Protein Therapeutics Across the Blood-Brain Barrier with Molecular Trojan Horses

WilliamM.Pardridge,M.D.,isDistinguishedProfessorofMedicineatUCLA.Hehasbeenstudyingblood-brainbarrier(BBB)transportsince1970.HsworkincludesthephysiologyandpharmacologyofBBBtransportofsmallmolecules,viacarrier-mediatedtransport,andlargemolecules,viareceptor-mediatedtranscytosis.Dr.PardridgeinventedthefieldsofmolecularTrojanhorsesforBBBdrugdeliveryofrecombinantproteins,theTrojanhorseliposometechnologyforintravenousnon-viralgenetherapyofthebrain,andthefieldofBBBgenomics.Hehasauthoredover400publicationsonthefieldofBBBdrugandnon-viralgenedelivery.Hismostrecentworkfocusesonthere-engineeringofbiopharmaceuticals for targeted drug delivery across the human BBB.

Michel Pettigrew, MBA | President of the Executive Board & Chief Operating Officer, Ferring PharmaceuticalsPanel Introductions & Panelist

Mr.PettigrewjoinedFerringinMay2001.InadditiontohisroleasPresidentoftheExecutiveBoard,heisresponsibleforallCommercial,GlobalMarketing,CorporateCommunications,BusinessDevelopment,MedicalServices,TechnicalOperationsandResearch activities of the Company. He is also President and CEO of Ferring Holding US,Ferring’slargestsubsidiary,andisresponsibleforallClinicalDevelopmentandCommercialactivitiesintheUnitedStates.PriortohisarrivalatFerring,Mr.Pettigrewheldseveralseniormanagementpositionsthroughouttheworldduringa21-yearcareerwithBristol-MyersSquibb.

MichelPettigrewhasaBachelorofCommercedegreefromMcGillUniversityinMontrealandaMBAfromYorkUniversityinToronto,Canada.

Pierre Rivière, Ph.D. | President & Director, Peptide Therapeutics Foundation; President, Ferring Research Institute & Senior Vice President, ResearchClosing Remarks

Dr.RivièreisresponsibleforglobalresearchatFerringPharmaceuticalsandfortheFerringResearchInstitute.Dr.RivièrejoinedFerringin1996asHeadofBiologybeforebecomingDirectorofResearch(2002),VicePresident,Research(2006)andSeniorVicePresident,Research(2010).Inrecentyears,Dr.Rivièrehascontributedtothediscoveryofseveralpeptidenewchemicalentities,nowatvariousstageofdevelopment,eitherinhouseorthrough licensees. He previously led the Gastroenterology drug discovery department of theInstitutdeRechercheJouveinalinFresnes,France.Dr.RivièreholdsaPh.D.inBiologyandPhysiologyfromtheInstitutNationalPolytechniqueofToulouse,France,andhascompletedapost-doctoraltrainingintheDepartmentofPharmacologyattheUniversityofArizonainTucson,Arizona.Dr.Rivièreisaco-founderofCaraTherapeutics,BioHeatMap,the Peptide Therapeutics Foundation and the Annual Peptide Therapeutics Symposium. Since2008,healsoservesasDirectorandPresidentofthePeptideTherapeuticsFoundation.


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Peter Schultz, Ph.D. | Scripps Family Chair Professor, Department of Chemistry, The Scripps Research InstituteAn Expanding Genetic Code

Peter G. Schultz graduated from Caltech in 1979 and continued there for his doctoral degree(in1984)withProfessorPeterDervan.AfterapostdoctoralyearatMIT,hemovedtotheUniversityofCalifornia,Berkeley,wherehewasaProfessorofChemistry,aPrincipalInvestigatorattheLawrenceBerkeleyNationalLaboratoryandanInvestigatorintheHowardHughesMedicalInstitute.HemovedtoTheScrippsResearchInstitutein1999whereheiscurrentlytheScrippsProfessorofChemistry.Schultz’sscientificcontributionsinclude:(1)thediscoveryofcatalyticantibodies,andtheirusetostudyfundamentalmechanismsofbiologicalcatalysisandtheevolutionofbindingandcatalyticfunction;(2)thedevelopmentandapplicationofmethodstoaddnewbuildingblockstothegeneticcodesofprokaryoticandeukaryoticorganisms;and(3)thedevelopmentandapplicationofmoleculardiversitytechnologiestoproblemsinchemistry,medicine,andmaterialsscience.Schultz also established the Genomics Institute of the Novartis Research Foundation in1999inLaJolla(andservedasitsDirectoruntil2010),whichdevelopsandappliesstateofthearthighthroughputchemical,proteomics,andgenomicstechnologiestothedevelopmentofnewhumantherapeuticsforcancer,immune,metabolic,cardiovascularand infectious disease.

Schultzistheauthorof~450scientificpublicationsandhasreceivednumerousawardsincludingtheAlanT.WatermanAward,NSF(1988),theACSAwardinPureChemistry(1990),theU.C.BerkeleyCollegeofChemistryTeachingAward(1992),theWolfPrizeinChemistry(1994),thePaulErhlichandLudwigDarmstaedterAward(2002),andtheACSArthurC.CopeAward(2006).ProfessorSchultzisamemberoftheNationalAcademyofSciences,USA(1993)andtheInstituteofMedicineoftheNationalAcademyofSciences(1998).HeisafounderofAffymaxResearchInstitute,SymyxTechnologies,Syrrx,Kalypsys,Phenomix,Ilypsa,Ambrx,WildcatDiscoveryTechnologies,andArdelyx,whichhavepioneeredtheapplicationofmoleculardiversitytechnologiestochallengesinenergy,materials and human health.

Jonathan Sweedler, Ph.D. | Professor of Chemistry, James R. Eiszner Family Chair, University of Illinois, Urbana-ChampaignNeuropeptidomics: From the Discovery of New Neuropeptides to the Elucidation of their Functions

Professor Jonathan V. Sweedler holds the James R. Eiszner Family Chair in Chemistry attheUniversityofIllinois,isassociatedwiththeBeckmanInstitute,isthedirectoroftheUIUCBiotechnologyCenter,andhasappointmentsintheNeuroscienceProgram,theDepartmentofPhysiologyandtheBioengineeringProgram.Hisresearchinterestsfocusonnewmetabolomicandpeptidomicapproachesforassayingsmallvolumesamples,and in applying these methods to study novel neurochemistry. He has received numerous awardsincludingtheFieldsAward,theMerckPrize,theInstrumentationAwardfromtheAnalyticalDivisionoftheAmericanChemicalSociety,theGillPrizeandtheBenedetti-PichlerAwardforMicroanalysis,andheisanassociateeditorforAnalyticalChemistry.


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Steven Taylor, Ph.D. | Director of Chemistry, Amylin Pharmaceuticals; Research Associate, Scripps Institution of OceanographyHigh Resolution Mass Spectrometry-Based Profiling of Secreted Peptides for Drug Discovery

StevenTaylorreceivedhisPh.D.inChemistryfromtheUniversityofQueensland,Australiaandcompletedhispost-doctoraltrainingattheUniversityofCalifornia,Davis,theUniversityofDelawareandsubsequentlyasanAlexandervonHumboldtResearchfellowattheUniversity of Tübingen in Germany. Steve was an Assistant Professor in Philadelphia for oneyearthenmovedtoSanDiegotojointheresearchfacultyattheScrippsInstitutionofOceanography(SIO).Hisresearchgroupfocusedonmarineantimicrobialpeptidesandtheelucidationoftheirpost-translationalmodificationsandmechanismofaction.Stevejoinedthebiotechindustryin2001,firstleadingamitochondrialproteomicsprogramatMitoKorinSanDiego,andsubsequently,ahigh-resolutionmassspectrometry-basedpeptidediscoveryprogramatAmylinPharmaceuticalsInc.whereheiscurrentlyaDirectorintheChemistrydepartment. He also continues as a Research Associate to SIO.

Willem van Werperen, MSc, MBA | CEO, to-BBBEndogenous Peptides to Safely Enhance the Delivery of (peptide) Drugs to the Brain

WillemobtainedaMScdegreeinbiomedicalsciencesfromUtrechtUniversity,andanExecutiveMBAdegreefromNIMBAS/BradfordUniversity.HebeganhisprofessionalcareerinclinicalresearchatGlaxoandjoinedGenzymein1994invariousEuropeanclinical,sales&marketingpositions.From2004to2006hewasgloballyresponsibleformarketingofthegeneticdiseasebusinessunitinGenzyme’sworldwideheadquartersinCambridge,MA.In2006WillemmovedbacktoleadtheGenzymeNetherlandsorganizationinNaarden.

In2009hejoinedtheto-BBBteamastheirCEOtohelpdeveloptheirbreak-throughbraindelivery platform for patients with CNS diseases. to BBB is a clinical stage private company inLeidenfocusingonenhanceddrugdeliveryacrosstheblood-brainbarrier.Thecompanyisdevelopingnoveltreatmentsfordevastatingbraindisorders,suchasbraincancer,neurodegenerativediseasesandlysosomalstoragediseases,bycombiningexistingdrugswith the G Technology®,toBBB’sproprietarybraindeliveryplatform.toBBBisapplyingtheG Technology® for the delivery of doxorubicin for the treatment of brain cancer as its internal leadproduct2B3101.ThisproductiscurrentlyinvestigatedinaphaseI/IIclinicaltrial.Asecondproductforneuroinflammation2B3-201isaimedtofollowthesameroute.Togetherwithseveraltoptierpharmaandbiotechcompanies,toBBBisfurtherinvestigatingtheversatility of the G Technology® for drugs that are unable to reach the brain within a tolerable therapeutic window.


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Ryan Watts, Ph.D. | Associate Director, Head of Neurodegeneration Labs, Department of Neuroscience, Genentech, Inc.Enhancing CNS Uptake of Biologics through Molecular Engineering

Dr.RyanJ.WattsistheAssociateDirectorandHeadoftheNeurodegenerationLabsintheDepartmentofNeuroscienceatGenentech.Dr.WattsjoinedGenentechin2004andinitiated a program exploring molecules that coordinate the development of both the vascular andnervoussystemsandtodefinetheirroleincancerandaxonregeneration.TheseearlyeffortsintheWattslabproducedaclinicalcandidateforcancer.In2006,Dr.Wattsinitiatedandledresearchprogramsintwobroadareas,neurodegenerationandtheblood-brainbarrier.Dr.WattswastheleadscientistandchairofajointresearchpartnershipwithACImmune that produced a clinical candidate for Alzheimer’s disease currently phase II clinical testing.

Dr.WattsisnowleadingalargegroupofscientistsintheNeurodegenerationLabs,whichfocusonstudyingthebasicbiologyof,anddevelopingtherapeuticsforneurodegeneration,withanemphasisonAlzheimer’sandParkinson’sdisease.Inadditiontostudyingneurodegeneration,Dr.Watts’ownlabisexploringtheestablishmentandmaintenanceoftheblood-brainbarrierandtheabilityofmoleculestotransversethisphysiologicalbarrier.

Dr.WattsreceivedhisPh.D.fromtheDepartmentofBiologicalSciencesatStanfordUniversity,wherehefocusedonneuronalremodelingviadegenerativemechanismduringnervoussystemdevelopment.Dr.WattsreceivedhisundergraduatetrainingformUniversityof Utah with a B.S. in Biology.

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6th Annual Peptide Therapeutics SymposiumNotes

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Abstracts 6th Annual Peptide Therapeutics Symposium

Abstracts of Lecture Presentations6th Annual Peptide Therapeutics Symposium

PhotocourtesyofthelaboratoryofSaraCourtneidge,Ph.D.,Professor,

Sanford-BurnhamInstituteforMedicalResearch,LaJolla,CA

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NPY2R Selective Peptide Agonists for the Treatment of Obesity: Balancing Efficacy, Time Action and Cardiovascular Profile

Jordi Alsina, Ph.D. | Senior Research ScientistEliLilly&CompanyLillyCorporateCenter,Indianapolis,IN46285|(317)276-8817 PYY along with NPY and PP are homologous members of the pancreatic polypeptide fold family characterized by a 36 amino-acidprimarysequenceandaC-terminaltyrosineamide.ThethreealsoshareauniquetertiarystructuralmotifcalledthePP-fold,consistingoftwoanti-parallelhelicesthatareoperativeintheirinteractionwithNPYreceptors.PYYissecretedbyendocrineL-cellsfromthedistalgastrointestinaltractinproportionalresponsetonutrientintake.TheactionofDPP-IVconvertstheparentsequenceintothetruncated3-36formwhichexhibitsenhancedselectivityforthepre-synapticterminaloftheNPY2R.ExtensivepreclinicalevidencehasestablishedPYY3-36/NPY2Raxisasanimportantmediatorofappetiteandenergybalance.RecentstudieshavecorrelatedPYY3-36/NPY2Rsignalingimpairmentwithageneticpredispositiontowardthedevelopmentofobesity.WhileseveralclinicaltrialsinnormalweightandobesesubjectshaveconfirmedapotentialtherapeuticutilityofPYY3-36asastand-aloneanti-obesityagent,additionalreportssuggestthatPYY3-36mayalsoenhancetheanorecticeffectsof(whenco-administeredwith)otherpeptidehormones.

Ourstructure-activitystudiesutilizedbothPYYandPPpeptidebackbonesasstartingpointstodevelophighlyselectiveY2agonists.Modificationwithpolyethyleneglycol(PEG)usinganovelN-terminallydirectedligationstrategyproducedaseriesofpotent,chemically-stable,andlongactingY2agonists.Theseanalogsweretestedinwell-establishedrodentobesitymodelsforefficacyandinanon-humanprimatemodelforcardiovascularsafety.

Development of a Long-acting C-peptide (ErsattaTM)

James Callaway, Ph.D. | President and CEOCebix Incorporated1298ProspectStreet,Suite2A,LaJollaCA92037|(858)729-6502

C-peptiderepresentsthelong-neglectedsecondpeptidethatisproducedinequimolaramountswithinsulininresponsetoconsumptionofcarbohydrate.Inthepasttwodecades,substantialdatahasbeenaccumulatedsuggestingthatC-peptideactsasahormonetoassureadequatesupplyofnutrients(primarilythroughvasodilation)tothecellsthroughoutthebodyastheytakeupcirculatingglucoseinresponsetoco-expressedinsulin.InthisregardtheC-peptide/insulindualhormonestorymirrorsthatofGLP-1/GLP-2/glucagon.IthasbeenproposedthattheabsenceofC-peptideintype1diabetespatientsisanimportantfactorintheearlyonsetandprecipitousadvancementofassociatedlong-termcomplicationsofthedisease.Totestthishypothesis,severalpreclinicalstudiesinanimalmodelsoftype1diabetesaswellasclinicalstudieswithC-peptidetreatment up to 6 months have been completed. These studies demonstrated positive clinical signals in diabetic peripheral neuropathythroughanimprovementinnerveconductionvelocityandglobalneuropathyscore.Additionally,areductionin microalbuminuria and improvement of glomerular structural abnormalities were observed in diabetic nephropathy after C-peptideadministration.EffortstodevelopanattractiveproducttoreplacecirculatinglevelsofC-peptidehavebeenstymiedbyitsshorthalf-life(»1hour)andtheneedforsubcutaneousdelivery.Cebixhassuccessfullycompletedadevelopmentprogramtogeneratealong-actingproductwithsubcutaneousdelivery(Ersatta).Theplantoconfirmtheextendedhalf-lifeofErsattainahumanpharmacokineticstudyandsubsequentlydemonstrateefficacyandsafetyinastudyoftype1diabetespatients with peripheral neuropathy will be presented.

EPiC Technology: Using Peptide to Physiologically Cross the BBB

Jean Paul Castaigne, M.D., MBA | President and CEO AngioChem201President-Kennedy,SuitePK-R220,Montreal,PQH2X3Y7,Canada|(514)788-7800

AngiochemisutilizingitsproprietaryEPiCplatformtocreateanddevelopdrugsthatphysiologicallycrosstheblood-brainbarrier(BBB).TheplatformhasbeenvalidatedinhumanintwoUSclinicaltrialswithitsleadcompoundGRN1005forthetreatment of brain metastasis and glioblastoma. This product was licensed to Geron Corporation and is now entering in PhaseIIpivotalclinicaltrials.Furthervalidationwereobtainedfromseveralpre-clinicalstudieswhichdemonstratedthebroadapplicabilityofthetechnologyfromsmallmoleculestobiologics(peptides,proteins,MAbs,etc).TheEpictechnology


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isbasedonafamilyofover100proprietarypeptidescalledAngiopepthatareallligandtotheLRP-1receptor,oneofthemostexpressedreceptorontheBBB.Onceattachedtothereceptor,theAngiopeparenaturallytransportedtothebrainviareceptor-mediatedtranscytosis.TheEpiccompoundcombinesanAngiopeptoadrugcandidate,creatinganewchemicalentity.Thisnewdrugcrossestheblood-brainbarrierthankstotheAngiopepandonceinthebrain,thedrugmoietycanactagainst brain diseases. The average increase in brain penetration of the EPiC compound compared to the native moiety range from 10 to 100 fold. Angiochem is developing its platform and its portfolio in wide varieties of indications including brain cancers,pain,obesity,Parkinson’sandothers.AngiochemforwardstrategyistomovesomeprojectsinternallytoPOCandtolicensethemand,inparallel,toestablishcollaborationwithcompanieshavingdrugcandidatesactivesagainstsomebraindiseases but not crossing the BBB.

Development of CR845, a Novel, Peripherally-Acting Peptidic Kappa Opioid Agonist, for the Treatment of Postoperative Pain

Derek Chalmers, Ph.D., D.Sc. | President & CEOCaraTherapeutics,Inc.OneParrottDrive,Shelton,CT06484|(203)567-1501

Eachyear,over100millionpeopleintheU.S.experiencepainfromsurgery,arthritis,cancer,neuropathies,orothermedicalconditions.Despitethishighprevalence,under-treatmentofpainremainsacriticalclinicalproblemduetothelimitedeffectivenessandsubstantialadverseeffectsofavailableanalgesics,includingcentrally-actingopiatesandNSAIDs.Wehavedevelopedanovelopioiddrugcandidate,CR845,designedtoproducepotentanalgesiaintheabsenceofcentralnervoussystemadverseevents.CR845isatetrapeptidekappaopioidreceptoragonistexhibitingpicomolaraffinityandgreaterthan30,000-foldselectivityovermuanddeltaopioidreceptors.Theall-D-aminoacidpeptidicstructureandaccompanyingphysicochemicalpropertiesofCR845distinguishthiscompoundfromthesmallmoleculeheterocyclekappaagonistsdevelopedtodate,allofwhichexhibitedsignificantadversecentralnervoussystemeffectsthatprecludedtheirfurther development as analgesics. Inbothsingleandmulti-dosei.v.studiesinhealthyvolunteers,CR845exhibitedlinearanddose-proportionalpharmacokinetics,withnoevidenceofmetabolismordrugaccumulation.CR845wasfoundtobesafeandwelltolerated,withnoincidenceofthedysphoricreactionsreportedpreviouslywithsmallmoleculekappaopioidagonists.Adouble-blind,placebo-controlledPhaseIIstudyofCR845inpatientsundergoingelectivelaparoscopichysterectomyindicatedthatasinglepost-operativedoseofCR845significantlyreducedpainintensityandneedformorphine.Inaddition,patientstreatedwithCR845exhibitedsignificantlylessopioid-relatedsideeffects,includingnauseaandvomiting.Asecondcontrolled200-patientPhaseIItrialiscurrentlyunderwaytoassesstheefficacyofCR845administeredbothpre-andpost-operativelyinthesamesurgical population.

Long Acting Y2R Peptide Mimetic as a New Generation Therapeutic Agent for the Management of T2D

Waleed Danho, Ph.D. | Distinguished Research LeaderHoffmann-LaRocheInc.RocheResearchCenter,Nutley,NJ07110|(858)461-0983

PYY1-36 isapeptidesecretedfromtheenteroendocrineL-cellsinthegastrointestinaltract,whichalsosecreteGLP-1.The

firsttwoaminoacidsofPYY1-36arecleavedbytheenzymeDPP-IVtogiverisetotheendogenousNPY2-receptor(Y2R)agonist,PYY3-36.Thelatterpeptidehasbeenshowntoreducefoodintakeinanimalmodelsofobesity,andleanaswellasobesehumans.However,PYY3-36reportedlydisplaysmodestselectivityagainstotherreceptorsintheNPY-receptorfamily.Moreover,PYY3-36hasaveryshortlifetimeincirculation.Thus,PYY3-36hasmajorlimitationsforbeingdevelopedintoatherapeuticentity.ThegoalofthisworkistodeveloplongactingagonistsoftheY2RtobeusedasatherapeuticagentsforthemanagementofT2Dandotherco-morbidities,withclear advantages in regards to efficacy/tolerabilitytoknownagents.

WeidentifiedanddevelopedanovelY2Rpeptidemimeticthatdemonstratesexcellentanti-diabeticeffectsaccompaniedwithsignificantweightloss.TheY2RmimeticexhibitsthefollowingkeydifferentiationfeaturesascomparedtoPYY3-36: a highly selectiveandlongactinganalogthatexertsacuteandsub-chronicanti-diabeticeffectsthatareindependentofbodyweightloss in diabetic db/dbmiceandZDFrats.Inaddition,thereispotentialforpancreaticbeta-cellpreservationasobservedin db/dbmice.Italsosubstantiallyreducedbodyweightgain,fatmassandlipidsinDIOrodents,andimprovedinsulinsensitization.Theidentificationanddevelopmentofthispeptidemimeticwillbepresented.

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Somatostatin-Dopamine Chimeric Molecules for Potential Treatment of Pituitary Adenomas and Neuroendocrine Tumors

Jesse Z. Dong, Ph.D. | Director, Peptide Therapeutics Foundation; Vice President, Compound DiscoveryIpsen27MapleStreet,Milford,MA01757|(774)396-6883

A novel class of chimeric compounds targeting growth hormone and prolactin secretions associated with pituitary tumors wasdeveloped.Theseconjugatescontainkeystructuralelementsofsomatostatinanddopamine.Theconjugatesinteractsimultaneouslywithsomatostatinanddopaminereceptorsubtypeslocatedonthesamecellsurface.Duetothesimultaneousengagementofbothreceptors,thecompoundsproducesignificantsynergisticeffectsintheinhibitionofbothgrowthhormoneandprolactinsecretions,notobservedbysomatostatinordopaminealoneorincombination.Thisclassofcompoundsmaypotentially represent a new treatment for pituitary adenomas and neuroendocrine tumors.

ZYPH0907: A Novel Orally Active PTH1R Agonist for Treatment of Osteoporosis

Mukul Jain, Ph.D. | Senior Vice PresidentZydus Research CenterSarkhej-BavlaN.H.No.8A,Moraiya,Ahmedabad382213,Gujarat,INDIA|+91-2717-665555Ext.511

Osteoporosisischaracterisedbydiminishedbonemineraldensity(BMD),reducedbonestrengthandincreasedriskoffracture.Parenteraladministrationofparathyroidhormone(PTH)increasesBMD,bonestrengthandreducesincidencesoffractures.PTHexertsitspharmacologicaleffectsduetointeractionwithPTH1R.Unfortunately,becauseoflargemolecularweightandmetabolicinstability,therapeuticapplicationofthispeptideviaoralrouteisnotpossible.Wehavedevelopedanovelorallybioavailablepeptidomimetic-basedPTH-1RagonistnamedasZYPH0907forthesafeandeffectivetreatmentofosteoporosis.

ZYPH0907isapotentandspecificagonistofPTH1R.InvitroassayusingUMR106cellsrevealedpotentPTH1RagonisticactivityofZYPH0907(EC50:35nM).Asinglep.o.doseofZYPH0907inthyroid-parathyroidectomized(TPTX)miceshoweddose-dependentincreaseintheserumcalciumlevels(ED50:4.39mg/kg).RepeateddailydosingofZYPH0907for14daysinovariectomizedSDratscauseddose-dependentincreaseinlevelsofboneformationbiomarkers,osteocalcinandPINP,whereasthelevelsofTRAP5b,aboneresorptionbiomarkerwerereduced.ZYPH0907wasfoundtobequitestableingastrointestinalfluidsandlivermicrosomes.Inpharmacokinetic(PK)studies,ZYPH0907showeddose-dependentoralabsorptioninmice,ratsanddogswithshorthalf-life.Inabatteryofsafetypharmacologystudies,ZYPH0907didnotshowanyadverseeffectrelatedtoCNS,CVSrespiratoryandGIparameterswhentestedatdosesthatareseveralfoldhigherthantheED50dose.Nooff-targetinteractionwasnoticed,whenZYPH0907wasscreenedagainstapanelofmorethan75moleculartargetsat10mMconcentrations.ZYPH0907wasfoundtobenon-mutagenicandnon-clastogenicingenotoxicitystudies.InacuteandrepeateddosetoxicitystudiesinWistarratsandbeagledogs,ZYPH0907waswelltoleratedandtheNOAELwasfoundtobeseveralfoldshigherthanefficacydose.Inthesestudies,theeffectsobservedwereeitherdirectlyorindirectlyrelatedtotheknownpharmacologicalactionsofPTHandwerefoundtobereversibleuponcessationofthetreatmentoveraperiodoftwoweeks.

Inconclusion,ZYPH0907representsanovelandorallyactivePTH-1Ragonistforthesafeandeffectivetreatmentofosteoporosis.

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Comparative Peptidomic Analysis for Functional Discovery of Neuropeptides

Lingjun Li, Ph.D. | Professor, School of Pharmacy and Department of ChemistryUniversity of Wisconsin777HighlandAvenue,Madison,WI53705-2222|(608)265-8491

Allnervoussystemsemployalargenumberofamines,aminoacidsandneuropeptidesasneurotransmittersandneuromodulators.Usingahighlysensitivemassspectrometry(MS)-basedpeptideprofilinganddenovosequencingstrategy,morethan200neuropeptideshavebeendiscoveredinawell-definedcrustaceannervoussystem,revealingthatevenarelativelysimpleneuralnetworkcontainsanunexpectedly-richdiversityofneuropeptides.Tofurtherexplorethefunctionoftheseneuropeptides,anaffinityenhancedinvivomicrodialysissamplingtechniquethatutilizeantibody-linkedmagneticnanoparticlesisexploredtoimprovepeptiderecoveryfromextracellularfluids,thusenablingLC-MSmonitoringofneuropeptidesecretionduringbehavior.Furthermore,binaryisotopiclabelingtechniquebasedonformaldehydelabelinganda multiplexed set of isobaric labeling reagents based on dimethylated amino acids have been developed and employed to produce differential display of neuropeptidomes under different physiological conditions. Examples of neuropeptide regulation offeedingbehaviorandneuralnetworkdevelopmentwillbehighlightedinthispresentation.Collectively,thesecombinedpeptidomic and physiological studies will help to elucidate the functional roles that neuropeptides play in regulating neural networkplasticity.

Targeting Protein Therapeutics Across the Blood-Brain Barrier with Molecular Trojan Horses

William M. Pardridge, Ph.D. | Distinguished Professor of MedicineUniversityofCalifornia,LosAngelesUCLAWarrenHall(13-164),900VeteranAve.,LosAngeles,CA90024|(310)825-8858

Biopharmaceuticals,includingrecombinantproteinsandmonoclonalantibodytherapeutics,cannotbedevelopedasdrugsforthebrain,becausetheselargemoleculesdonotcrosstheblood-brainbarrier(BBB).Biopharmaceuticalscanbere-engineeredtocrosstheBBB,andthisispossiblewiththeengineeringofIgGfusionproteins.TheIgGisapeptidomimeticmonoclonalantibody(MAb),whichactsasamolecularTrojanhorse(MTH)thatferriesthefusionproteinacrosstheBBBviareceptor-mediatedtransportonendogenousBBBreceptors.ThemostpotentBBBmolecularTrojanhorseisaMAbagainstthehumaninsulinreceptor.MTHfusionproteinshavebeenengineeredandvalidatedforneurotrophins(erythropoietin,GDNF),decoyreceptors(TNFR),singlechainFvantibodies(againsttheAbetapeptide),andlysosomalenzymes(iduronidase,iduronate2-sulfatase).Peptides,thatarenotcandidatesforMTHfusionproteins,maybere-engineeredforBBBtransportwiththecombinationofMTHfusionproteinandavidin-biotintechnology.Theco-injectionofthemono-biotinylatedpeptideandanMTH-avidinfusionproteinenablesbrainpenetrationofpeptidetherapeutics.

An Expanding Genetic Code

Peter Schultz, Ph.D. | Scripps Family Chair Professor, Department of Chemistry The Scripps Research Institute10550NorthTorreyPinesRoad,SR202,LaJolla,CA92037|(858)784-9300

Thedevelopmentofneworthogonalaminoacyl-tRNAsynthetase/tRNApairshasledtotheadditionofapproximately70unnaturalaminoacids(UAAs)tothegeneticcodesofEscherichiacoli,yeast,andmammaliancells.TheseUAAsrepresenta wide range of structures and functions not found in the canonical 20 amino acids and thus provide new opportunities to generate proteins with enhanced or novel properties and probes of protein structure and function.

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Neuropeptidomics: From the Discovery of New Neuropeptides to the Elucidation of their Functions

Jonathan Sweedler, Ph.D. | Professor of Chemistry, James R. Eiszner Family Chair UniversityofIllinois,Urbana-Champaign600S.MathewsAve.,63-5,Urbana,IL61801|(217)244-7359

Neuropeptides are critical molecules that modulate the physiological activity of almost every neuronal circuit in the brain. Surprisingly,though,moreandmorebrainpeptidesarebeingdiscovered.Eventherateofbrainpeptidediscoveryisaccelerating.Whatdothesenovelpeptidesdo?Twomajorareasareaddressedhere,onetechnicalandonebiological.Thefirstareahighlightsmassspectrometry-basedtechnologiestocharacterizethebrainpeptidesfromsamplesrangingfrombrainregionstosinglecells.Usingthesecutting-edgemassspectrometry-basedapproaches,wegeneratelistsofknownanduniquepeptidesfromspecificbrainregions,withtheselistsreachingtohundredsofpeptides.Evenforsmallbrainareas,westilldetecthundredsofpeptides,makingfollow-upstudiesdaunting.Thesecondareaaddressesthequestionofwhichpeptidesareworthextensivefollow-upstudies.Usingthesuprachiasmaticnucleus(SCN)asanexample,wedescribefunctionalstudiessuchasmeasuringthepeptidesreleasedfromtheSCNinanactivitydependentmannerandatspecifictimesoftheday.Knowingthatanovelpeptideisonlydetectableataspecifictimeofthedayorunderspecificelectricalstimulationprotocolsyieldscriticalinformationonpotentialpeptidefunction.Forexample,theSCNpeptide“littleSAAS”exhibitsrobustretinohypothalamictract–stimulatedreleasefromtheSCN,andexogenousapplicationoflittleSAASinducesaphasedelayconsistentwithlight-mediatedcuesregulatingcircadiantiming.Inothercases,well-knownbrainpeptidesareshowntohaveunique functions. Several additional examples of neuropeptide discovery are described across a range of metazoan life.

High Resolution Mass Spectrometry-Based Profiling of Secreted Peptides for Drug Discovery

Steven Taylor, Ph.D. | Director of ChemistryAmylinPharmaceuticals,9360TowneCentreDr.,SanDiego,CA92121|(858)458-8550ResearchAssociate,ScrippsInstitutionofOceanography

Peptidehormonesderivedfromtheneuroendocrinesystemhavegreattherapeuticvaluebecauseoftheirhighactivity,specificityandlowtoxicity.Traditionally,characterizationofnaturalpeptideshasinvolvedcollectionofalargeamountofsourcematerialfollowedbylaborioussubfractionationfollowingspecificactivityassays.Massspectrometric-basedtechniques,coupledwithgenomicinformationandnewinformaticalgorithms,haveacceleratedtheprocessofpeptidecharacterizationfromminutequantities.WeadoptedastrategycalledthePHASST-MSapproach(PeptideHormoneAcquisitionbySmartSamplingTechniques-MassSpectrometry)involvinganalysisofsecretedpeptidesfromtissueenrichedinendocrinecellse.g.frompancreaticisletsandguttissue.Incontrasttoanalysisofcellularlysates,thestudyoflivingcellsisadvantageousbecause(a)theyareresponsivetophysiologicalandpharmacologicalstimuliand(b)lessintracellularproteinbackgroundisproducedwhichcanmaskthedetectionofsecretedpeptides.Minimalsamplemanipulationminimizedadsorptivelossoflowabundancepeptideswhichweresimplydesalted,concentratedanddirectlyanalyzedbyhighresolutionLC/MS.Peptideidentity was established through a variety of gas phase fragmentation techniques from which amino acid sequence was derivedbyMSinformatics.Theuseofmassmapsforrelativequantification,allowedustoseedifferencesinpeptideprofilesreflectiveofcellularstate(e.g.stimulatedorunstimulated,diseasedorhealthy).Byadoptingpeptidomicratherthanproteomicapproacheswheretrypsindigestionisemployed,wecapturedfulllengthposttranslationally-processedpeptides<1to16kDaratherthanproteolyticfragmentsforidentification(i.e.a“topdown”approach).ThePHASST-MScollectionrepresentsasubsetofAmylin’sproprietaryPHORMOLlibraryandhasbeensynthesizedbylowandhighthroughputtechniquesforassessmentofbioactivity through in vitro and in vivo screening.

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Endogenous Peptides to Safely Enhance the Delivery of (peptide) Drugs to the Brain

Willem van Werperen, MSc, MBA | CEO to-BBBNielsBohrweg11,2333CALeiden,TheNetherlands|+31713322252

Peptidesarepromisingcandidatesforthetreatmentofsomecentralnervoussystem(CNS)disorders.InordertoachieveCNS-effects,theymustbeabletoeffectivelycrosstheblood-brainbarrier(BBB).ThedistributionofpeptidesacrosstheBBBishoweveroftenlimitedduetotheirhydrophilicproperties,andshorthalf-lifeinplasma.

Theendogenoustripeptideglutathione(GSH)isfoundathighlevelsinthebrainandisactivelytransportedacrosstheblood-brainbarrier.Glutathione-conjugatedpegylatedliposomeswerefoundtomediatesafetargetingandenhanceddeliveryofencapsulated drugs to the brain.

to-BBBisdevelopingglutathionepegylatedliposomaldoxorubicinforpatientswithbraincancer.Theproductisbasedonthemarketedpegylatedliposomaldoxorubicin(Doxil),andwasshowntobesuperiorinincreasingbrainuptakeandreducingbraintumorgrowthinexperimentalmodels.Thefirstclinicaltrialinpatientswithbrainmetastaseswasinitiatedmid2011.

Asecondproductindevelopmentisglutathionepegylatedliposomalmethylprednisolone(2B3-201)forthetreatmentofneuroinflammation.2B3-201wasshowntohavesuperiorefficacyoverfreemethylprednisoloneatamuchlowerdose,andalsoover(non-targeted)pegylatedliposomalmethylprednisolone.

AnotherprojectaimstostudythedistributionofapeptideacrosstheBBBonitsownandencapsulatedintotheglutathionepegylatedliposomesbyusingsimultaneousbloodandbrainmicrodialysis.Thesteady-stateunboundplasmaconcentrationswerekeptidentical,whiletheliposomessignificantlyincreasedbrainpeptidedelivery.

Finally,invitroexperimentswereperformedwithdextran-FITC(4kDa)encapsulatedinglutathionepegylatedliposomesand(non-targeted)pegylatedliposomes.Asignificant5-foldhigheruptakeofGSH-coatedliposomeswasobservedusingmicroscopyandcelllysates.Thisspecificuptakewasliposomesizeandtemperaturedependent,indicativeofanactiveendocytoticuptakeprocess.

Inconclusion,glutathionepegylatedliposomesofferapromisingplatformforsafelyenhancingthedeliveryof(peptide)drugstothe brain.

Enhancing CNS Uptake of Biologics through Molecular Engineering

Ryan Watts, Ph.D. | Associate Director, Head of Neurodegeneration Labs, Department of NeuroscienceGenentech,Inc.1DNAWay,MS-212,S.SanFrancisco,CA94080|650-467-8197

Utilizingreceptor-mediatedtranscytosis(RMT)pathwaystocrosstheblood-brainbarrier(BBB)hasbeenexploredforseveraldecadesasamechanismtoincreaseproteindeliverytothebrain.Nevertheless,manyhavediscoveredthatantibodiestargetingRMTpathways,particularlytransferrinreceptor(TfR),accumulateinCNSvasculatureandfailtocrosstheBBBinappreciableconcentrations.WehavediscoveredthatreducingtheaffinityofanantibodyfortheTfRenhancesRMToftheanti-TfRantibodyacrosstheBBBintothemousebrainwhereitreachestherapeuticallyrelevantconcentrations.Anti-TfRantibodiesthatbindwithhighaffinitytoTfRremainassociatedwiththeBBB,whereaslower-affinityanti-TfRantibodyvariantsarereleasedfromtheBBBintothebrainandshowabroaddistribution24hoursafterdosing.WedesignedabispecificantibodythatbindswithlowaffinitytoTfRandwithhighaffinitytotheenzymeb-secretase(BACE1),whichprocessesamyloidprecursorproteinintoamyloid-beta(Abeta)peptidesincludingthoseassociatedwithAlzheimer’sdisease.Comparedtomonospecificanti-BACE1antibody,thebispecificantibodyaccumulatedinthemousebrainandledtoagreaterreductioninbrainAbetaafterasinglesystemicdose.TfR-facilitatedtranscytosisofthisbispecificantibodyacrosstheBBBmayenhanceitspotencyasananti-BACE1therapyfortreatingAlzheimer’sdisease.

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Notes 6th Annual Peptide Therapeutics Symposium

31

Posters 6th Annual Peptide Therapeutics Symposium

Abstracts of Posters6th Annual Peptide Therapeutics Symposium

PhotocourtesyofthelaboratoryofPamelaItkin-Ansari,Ph.D.,AdjunctAssistant

Professor,Sanford-BurnhamMedicalResearchInstitute/UCSD,LaJolla,CA

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P 01 Site-specific Antibody-Drug Conjugates by Genetically Incorporated Unnatural Amino AcidsJun Y. Axup1,BenjaminM.Hutchins1,KrishnaM.Bajjuri2,MelissaO’Neal3,ChanHyukKim1,StephanieA.Kazane1,RajkumarHalder1,JaneS.Forsyth3,YingchunLiu4,HonTran4,AaronSeller4,BradHehli4,WeixingChen4,SemsiEnsari4,SandraBiroc4,AgaSzydlik4.JasonPinkstaff4,FengTian4,SubhashC.Sinha2,BrunhildeFelding-Habermann3,VaughnV.Smider2,PeterG.Schultz1

Departmentsof1Chemistry,2MolecularBiology,3MolecularandExperimentalMedicine,TheScrippsResearchInstitute,10550NorthTorreyPinesRoad,LaJolla,CA920374Ambrx,Inc.,10975NorthTorreyPinesRoad,LaJolla,CA92037

Antibody-drugconjugatescanselectivelydeliverdrugstocellspresentingtumorassociatedsurfacemarkerstherebyreducingsystemictoxicity.Traditionally,proteinconjugationsaredonethroughcysteineorlysineresidues,butthesechemistriesoftenleadtoheterogeneousproductsandprocesschallengesinscale-up.Wedemonstratetheuseofgeneticallyencodedunnaturalaminoacidswithuniquechemicalreactivitytofacilitatetheconstructionofantibody-drugconjugatesandprovidesite,stoichiometry,andhomogeneitycontrol.AnorthogonaltRNA/aminoacyl-tRNAsynthetasepairisusedtosite-specificallyincorporatep-acetylphenylalanineinresponsetoanambercodoninFabfragments,madeinE.coli,andfull-lengthIgG,inmammaliancells.WeconjugatemonomethylauristatinEtotrastuzumab(anti-Her2)anddemonstrateeffectiveinvitroandinvivocytotoxicity.Ourtechnologycanbeexpandedtoanysite-specificconjugationofproteintopeptides,DNA,orsmallmolecules.

P 02 Challenges in Insulin PurificationAndersTorncrona,BrittKofoed-Hansen,Jared W. BenedictandP.K.DuttaAkzoNobelN.V.

Reversedphaseliquidchromatography(RPLC)hasproventobeaveryefficienttooltopolishcrudesolutionsofpolypeptides.Silica-basedreversedphasematerialsforpolypeptidepolishinghavebeenonthemarketformanyyearsnow.ThesinglelargestapplicationforpolypeptidepolishingbyRPLCisinsulinpurification.Overtheyears,therehavebeenmanyattemptsto“optimize”RPLCinsulinpurificationbytailoringthesilicabackboneand/orbondedphases. This poster illustrates the effects of silica pore size and bonded phase on the purity and recovery of human insulin. The adsorptioncapacityhasbeenmeasuredbyinsulinbreakthroughcurvesforvariousmaterials.Inadditiontothestandardsilicaonthemarketsomeprototypes,includingapHstablephase,wasincludedinthestudy.Theexplorationofexistingandnewmaterials shows the best phase for insulin purity and recovery in this study.

P 03 Bioanalysis of Therapeutic and Endogenous Peptides in Human PlasmaErinEChambers,JessalynPWheaton,KennethFountain,andDebadeepBhattacharyaWatersCorporation,Milford,MA01757

Thepurposeofthisstudyistodevelopaplatform-basedapproachforbioanalysisoftherapeuticandendogenouspeptides(includingbiomarkers)inhumanplasma.Asolidphaseextraction(SPE)screeningstrategyconsistingof1protocoland2mixed-modesorbentswasemployedtosimplifySPEmethoddevelopment.AnLCscreeningmethodwasdevelopedonalowdispersionsystem.MRMdetectionofmultiplychargedparentsandsinglyormultiplychargedfragmentswasperformedusingXevoTQ-StandemquadrupoleMSoperatinginESI+mode.

Thechromatographicsystemproducedpeaks2-4secondswideatbasefor12diversepeptidesusingthebasicLCscreeningprotocol.WithminormodificationstotheSPEmethodsfor3peptides,extractionrecoverybecame>82%forallpeptides.Absolutematrixeffectsfor8outof12peptidesweredetermined,andfoundtobe<11%.SPEwasperformedusingtheμElutionformat to minimize sample volume used and to concentrate analytes without evaporation and reconstitution. This improved detectionlimitsandeliminatedpotentialadsorptivelossesduringevaporationandreconstitution.Linearityover3.5ordersofmagnitudeandLOD/LLOQ’sinthepg/mLrangeisdemonstratedforrepresentativepeptides.Thisstudydescribesinitialsamplepreparationmethodsandchromatographicconditionsfor12diversepeptidetherapeutics/biomarkersusingtheLC,MS,andSPE screening methods described.

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P 04 Optimization of the Native Glucagon Sequence for Medicinal PurposesJoseph R. Chabenne,MariaA.DiMarchi,VasilyM.GelfanovandRichardD.DiMarchiDepartmentofChemistry,IndianaUniversity,Bloomington,IN47404USA Glucagonisalife-savingmedicationusedinthetreatmentofhypoglycemia.Itpresentsuniquestructuralchallengestotheidentificationofananalogofhighbiologicalactivityandselectivitythatalsopossessessufficientaqueoussolubilityandstability such that it might be developed as an emergency use medicine. At low and high pH the peptide can be formulated atamilligrampermilliliterbutthechemicalstabilityofthehormoneislimited,asevidencedbytheformationofmultipledegradationpeptides.Consequently,thecommercialpreparationisprovidedasalyophilizedsolidwithanacidicdiluentanddirectionsforrenderingitsolubleatthetimeofuse.Asetofglucagonanalogswaspreparedtoexploretheidentificationof a glucagon analog with enhanced solubility and chemical stability at physiological pH. We observed the previously characterizedformationofglucagondegradationproductsuponincubationofthepeptideindiluteacidforextendedperiods,orelevatedtemperature.Loweringtheisoelectricpointofthehormonethroughthesubstitutionofasparagine28withasparticacidsignificantlyincreasedthesolubilityatphysiologicalpH.Similarly,theC-terminalextensionofthehormonewithanexendin-based,ten-residueC-terminalsequenceyieldedapeptideofdramaticallyenhancedsolubility.ThesetwoglucagonanalogsD28andCEXmaintainedhighpotencyandselectivityfortheglucagonreceptorrelativetoGLP-1receptor.TheglucagonanalogsD28andCEXdemonstratedallofthechemical,physical,andbiochemicalpropertiessupportiveoffurtherstudy as potential clinical candidates for treatment of hypoglycemia.

P 05 An Expanded Self-Antigen Peptidome Is Carried by the Human Lymph As Compared to the PlasmaCristina C. ClementandLauraSantambrogioPathologyDepartment,AlbertEinsteinCollegeofMedicine;1300MorrisParkAvenue,Bronx,NY,10461

Thepre-nodalafferentlymphisthefluidwhichdirectlyderivesfromtheextracellularmilieufromeveryparenchymalorganand,asitcontinuestocirculatebetweenthecells,itcollectsproductsderivingfromtheorganmetabolism/catabolism.Acomprehensivequalitativeandquantitativeinvestigationoftheself-antigenicrepertoiretransportedbythehumanlymphisstillmissing.OurresultsshowedamajordifferencebetweenlymphandplasmathatcouldbevisualizedbyFPLCand2Dgelintheamountoflowmolecularweightproductscorrespondingtopeptidefragments.withMW<5000Da.Naturallyprocessedpeptidesinnormalpre-nodalhumanlymphwerethenfractionatedbyHPLCandcharacterizedbymultidimensionalnano-LC-MS/MSmassspectrometry.Analysisofmorethen300sequencesidentifiedself-peptidesderivedfrombothintracellularandextracellularproteinsrevealingthevarietyofcatabolicproductstransportedbyhumanlymph.Quantitativeanalysisestablished that at least some of these peptides are present in the circulating lymph in nanomolar concentration. The peptidome,generatedbyphysiologicaltissuecatabolismandtransportedbythepre-nodallymph,isinadditiontotheself-peptidomegeneratedinendosomalcompartment.UnlikeselfantigenprocessedbylocalornodalAPC,whichmostlyproduceepitopesconstrainedbytheendosomalprocessingactivity,selfantigenspresentinthelymphcouldderivedfromawidervarietyofprocessingpathways;includingcaspases,involvedincellularapoptosis,andADAMandothermetalloproteinasesinvolvedinsurfacereceptorediting,cytokinesprocessingandmatrixremodeling.Altogether,expandingthetissue-specificself-repertoireavailableforthemaintenanceofimmunologicaltolerance.

P 06 Rational Design, Synthesis and Structural Characterization of D-Phe-Pro-D-Arg-Derived Thrombin InhibitorsAna Carvalho Figueiredo#a,Cristina C. Clement#*b,SheuliZakiab,JulianGingoldc,ManfredPhilippb and Pedro José Barbosa Pereiraa* #TheseauthorscontributedequallytothisworkaIBMC-InstitutodeBiologiaMoleculareCelular,UniversidadedoPorto,4150-180Porto,PortugalbDepartmentofChemistry,LehmanCollege,&BiochemistryProgram,CUNYGraduateSchool,NewYork,NY10036,USAcMDProgramatMountSinaiSchoolofMedicine,NY

Novelhexapeptides,pentapeptidesandtetrapeptidesweredesignedusingin silicostructure-baseddesignapproachesandfurther tested for their ability to inhibit α-thrombin in vitro.InitialmoleculardockingexperimentsgeneratedacandidategroupofcompoundswithbothL-andD-aminoacids,containingtheD-Phe(P3)-Pro(P2)-D-Arg(P1)-P1’-P2’-P3’-CONH

2 sequence.

TheuseofD-ArgintheP1positionmadethedesignedpeptidesinhibitorsstabletoproteolysis.Thestructure-activityrelationshiprevealedtheleadcompoundsasbeingtetrapeptidesfromtheseriesD-Phe-Pro-D-Arg-P1’-CONH

2. The P1’

positionwasscannedwithLandD-isomerscoveringthemajorchemicalclassesofnaturalorunnaturalaminoacids,suchasL-2-thienylalanine(L-Thi).Theleadtetrapeptide,D-Phe-Pro-D-Arg-D-Thr-CONH

2,hasaK

iof0.85mM.Thethree-dimensional

structures of three complexes of human α-thrombinwiththreeleadpeptidicinhibitors(withL-isoleucine(p3),L-cysteine(p4)orD-threonine(p6)attheP1’positionoftheleadD-Phe-Pro-D-Arg-P1’-CONH

2sequence)weredeterminedbyX-ray

34


crystallography.Alltheinhibitorsbindinasubstrate-likeorientationtotheactivesiteofthrombin.TheX-rayanalysesofallthreecomplexesshowtheupstreamresiduessittingdeeperintheS2andS3pocketswhilethecleavablebondadoptsanunfavorablegeometryfornucleophilicattackbytheserinesidechain(3.69Å,2.85Åand2.96ÅdistancebetweentheSer195Oyandtheargininecarbonylcarbonforp3,p4andp6,respectively).Thus,ourcrystalstructuresofhumanα-thrombin complexeswithpeptidicinhibitorswithD-ArgintheP1positionprovideinsightsintothemainstructuralfeaturesthatenabledthem to be totally stable to proteolysis.

P 07 Design and Synthesis of Novel Bifunctional ligands (Bradykinin Antagonists and Opioid Agonist) for Treatment of Chronic and Neuropathic PainSrinivasDeekonda1,DavidRankine2,PegDavis2,JosephineLai2,FrankPorecca2,andVictorJHruby1

1DepartmentofChemistryandBiochemistry,UniversityofArizona,TucsonAZ-857212DepartmentofPharmacology,UniversityofArizona,Tucson,AZ85721,USA

Kininsarenaturallyoccurringvasoactivepeptideswhichareknowntobeimportantmediatorsofavarietyofbiologicaleffects,includingcardiovascularhomeostasis,inflammation,andnociception.ThekininfamilyincludesBradykinin,Kallidinandtheiractivemetabolitesdes-Arg-bradykininanddes-Arg-kallidin.ThebiologicalactionsofthesekininsaremediatedbytwomajorG-protein-coupledBradykininreceptors:B1andB2.OpioidreceptorsbelongtothebigfamilyofG-protein-coupledreceptorswhich mediates antinociceptive effects in humans. Here we designed and synthesized novel bifunctional ligands containing BradykininantagonistandOpioidagonistpharmacophore,thesenovelligandshavenovelbiologicalactivityprofileinpainpathways,whereintheOpioidpharmacophoreismaintainedtowardstheN-terminal. Opioidμ/dAgonists B2 Receptor AntagonistTyr-Pro-Phe-DArg-Arg-Pro-Hyp-Gly-Thi–Ser-DTic–Oic-ArgTyr-DAla-Gly-Phe-DArg-Arg-Pro-Hyp-Gly-Thi-Ser-DTic-Oic-Arg

1.SupportedbyagrantfromtheU.S.PublicHealthServiceNIDA2.Leeb-Lundberg,L.M.F.;Marceau,F.;Muller-Esterl,W.;Pettibone,D.J.;Zuraw,B.L.Pharmacol.Rev.2005,573.Dziadulewicz,E.Ann.ReportsinMed.Chem.39,113-121,2004

P 08 Enhanced Albumins and Albumin Fusion Technology, Albufuse®Flex – Tailored Circulatory Half-life to Meet Medical NeedsRandall EnglerNovozymesBiophamaUKLtd.

Amajorchallengeforthetherapeuticuseofmanypeptidesandproteinsistheirshortcirculatoryhalf-life.Albuministhemostabundantplasmaproteinandhasanextendedcirculatoryhalf-lifeduetoitssizeandFcRnrecycling,apropertysharedwithIgG.Recombinantfusionstoalbuminhavebeenshownintheclinictohavesignificantlyenhancedpharmacokineticswhilst retaining the bioactivity of the therapeutic peptide or protein. While the IgG:FcRn interaction is extensively mapped andmodificationstothisinteractionhavebeenshowntoimprovethepharmacokineticsofthesemodifiedantibodies,thecharacterisationofthealbumin:FcRninteractionisinitsinfancy.Aminoacidpositionshavebeenidentifiedwithinthealbuminsequence that allow the modulation of the albumin:FcRn interaction — this data set starts the process of mapping the entire albumin:FcRninteractionsurfaceleadingtothedefinitionofasmallerFcRnbindingsitewithinthealbuminstructure.Throughsubtlemodificationofthealbuminmoleculethisinnovativetechnologyaimstoprolongthecirculatoryhalf-lifeofthealbuminmoleculeitself,therebyconferringtheseadvantageouspropertiestoanyassociatedtherapeutic.Asaconsequencethismayallowscientiststheopportunitytotailortheirdrugdesigntofitthepatient’sspecificmedicalneeds,reducingdrugsideeffects,improvingpatientcomplianceandqualityoflife.Thepresentationwilldescribekeyadvancesinthedevelopingthenextgenerationalbuminfusion/conjugationhalf-lifeenhancingtechnologies.

P 09 In Vivo Targeting of Human Cancers with Radiolabeled Somatostatin AntagonistsJudit Erchegyi1,DamianWild2,MelpomeniFani2,PhilippT.Meyer2,ChristofRottenburger2,JeanClaudeReubi3,HelmutR.Maecke2 and Wolfgang A. Weber2,JeanE.F.Rivier11ClaytonFoundationLaboratoriesforPeptideBiology,SalkInstitute,LaJolla,California;2DepartmentofNuclearMedicine,UniversityHospitalFreiburg,Freiburg,Germany;3DivisionofCellBiologyandExperimentalCancerResearch,InstituteofPathology,UniversityofBerne,Berne,Switzerland

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Theuseofradiolabeledsomatostatinagoniststargetingneuroendocrinetumorsover-expressingsomatostatinreceptorsubtypes(sst

1-5)isanestablisheddiagnosticandtherapeuticprocedureinoncology.Weshowthatsimilarlyradiolabeledsomatostatin

antagonists,eventhoughtheydonotinternalize,canbebetterradioligandstotargettumorsthansomatostatinagonistswithcomparablebindingcharacteristics.Forexample,thesomatostatinagonist,111In-DOTA–[1-Nal3]-octreotidewithstrongsst

3-

bindingandinternalizationpropertiesshowedamuchlowerandshorter-lastinguptakeinmicebearingsst3 tumors than our sst

3-

selective antagonist 111In-DOTA-sst3-ODN-8.Similarly,thetumoruptakeofthesst

2-selectiveantagonist(111In-DOTA-BASS)was

considerably higher than that of a highly potent sst2-selectiveagonist111In-DTPA-TATEinmicebearingsst

2tumors.Additionally,

the sst2-selectiveantagonistsshowedmorelesions(111In-DOTA-BASS,16lesions,2.4injectedactivity(%IA),111In-DOTA-JR11,

36lesions,7.2%IA)thantheagonist111In-DTPA-octreotide(11lesions,1.3%IA).WehavealsoevaluatedwhetherDOTAorNODAGAchelator-coupledsomatostatinantagonistsareaffectedbythenatureoftheradiometal.Indeed,weshowthatcomplexationwithIn(III),Y(III),Lu(III),Cu(II)andGa(III)impactsbindingaffinityinanunpredictableway.Overall,theseresultsemphasizethefactthattheuseofbiologicallyactivepeptideantagonistsversusagonistswillsignificantlyaffectpeptidereceptor–mediated imaging and therapy.

P 10 Towards Orally Available Peptide TherapeuticsStephen Fiacco,TerryTakahashi,YoniPeleg,BiliangHu,ShannonHowell,RichardRoberts,PinWangEvoRxTechnologies,SouthPasadena,CA91030

Peptidesarepromisingnext-generationtherapeuticsexhibitinghighbindingspecificitiesandaffinities.However,theyareunstableinvivoanditisdifficulttorationallystabilizepeptideswithoutlossorchangeoffunction.Here,wedescribeanovelmRNAdisplayplatformtoevolvehighlystabilizedunnaturalcyclicpeptideswithpotentanti-tumorproperties.Wedesigneda20millionmemberlibrarythatincludedanon-naturalN-methylaminoacidandpre-selectedforstabilizedpeptidesbyexposuretoproteases.Theresultingpeptidesexhibiteda~500-foldimprovementinhumanserumstability(t

1/2=160hours).Simple

conjugationtoanon-toxic,smallmolecule,naturalproductallowedforefficientoraluptakeinvivo.WeusedthislibrarytoevolveligandstargetingtheoncogenicproteinHer-2bytargetinghumanbreastcancercellsoverexpressingHer-2.Twoligandsweretestedinabreastcancercellmodel,showing25%and44%inhibitionofgrowthwhenadministeredseparately,and61%inhibitionwhenadministeredtogether.Thisisincomparisonto25%inhibitionbyHerceptin.OurpeptidesdemonstratecomparableefficacytoHerceptininmousexenograftsasco-administrationoftheseligandsresultsinanaveragetumorsizereductionof>35%inmousexenograftsover4weeksoftreatment,whileuntreatedmousetumorsgrewto2.5timestheiroriginalsize.Thisworkprovidesaroadmapforthedevelopmentoforallybioavailablepeptidicligandswithexcellentstabilityandtherapeuticefficacyformultiplediseasestates.

P 11 Enhanced Efficacy in Treating the Metabolic Syndrome by Peptide-Directed Estrogen B. Finan1,B.Yang2,V.Gelfanov1,N.Ottaway3,P.Pfluger3,D.Perez-Tilve3,M.Tschöp3,andR.DiMarchi1. 1DepartmentofChemistry,IndianaUniversity,Bloomington,IN,47404,USA2MarcadiaBiotech,Carmel,IN,460323DivisionofEndocrinology,DepartmentofMedicine,MetabolicDiseaseInstitute,UniversityofCincinnati,Cincinnati,OH45237

Rodentandhumanclinicalstudiesestablishedthatestrogenpossessesrobustanti-diabeticandweight-loweringactions,however,theclinicalapplicationofestrogenislimitedduetothefearofitsoncogenicpotentialandgynecologicalaction.Toenhancethetherapeuticindexofestrogen,weexploredthepreferentialtargetingofestrogentodesiredtissueswhileminimizingactionatbreastandendometrialtissuesthroughtheuseofincretin-basedpeptideconjugates.BymarryingthepharmacologiesofGLP-1andestrogen,weenvisionaconstructivebeneficialeffectonglycemicandenergyhomeostasisbythecombinedinsulinotropicandanabolicactivitiesonpancreaticbetacellswithananorecticeffectatthehypothalamus.Asetofpeptide-estrogenconjugatesweresynthesizedtopossessfullGLP-1agonismwithabroadrangeofactivitiesandwithlinkerchemistriesthat enable differential estrogen release from chemical forms that are stable to other forms that fully release estrogen in a few hours.Inmetabolically-challengednon-diabeticmice,afullyactiveGLP-1agonistwithastably-linkedestrogenconsistentlyprovedtobemoreefficaciousinimprovingbloodglucoseandbodyweightthanthecomparativeGLP-1andestrogencontrolswhichlikelyresultsfromsynergistichormoneactionratherthanenhancedpharmacokinetics;however,themechanismbywhichthesebeneficialeffectsareachieved,particularlythetissuesofactionandestrogenreceptorsresponsible,remainsafocusofongoinginvestigation.Furthermore,thishighlypotentGLP-estrogenconjugateisdevoidofclassicalestrogenicactivityinendometrialtissuesasassessedbythelackofuterinehypertrophy,however,theoncogenicpotentialinbreasttissueiscurrentlybeing evaluated through xenograft studies.

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P 12 Anesthesiologists: The Primary Profession Which Delivers Peptide Therapeutics In The Clinic?EricR.GrossMD,PhD1,DariaMochly-RosenPhD2

Departmentof1Anesthesiology and 2ChemicalandSystemsBiology,StanfordUniversity

Anesthesiologistsarephysiciansthathaveintegralrolesacrosshospitalinfrastructure,includingprovidingservicesintheoperatingroom,obstetricsuite,intensivecareunit,painclinicsandduringcodesituations.Withpeptidetherapeuticshavingquickonset,specifictargetofaction,rapidmetabolism,minimaldrug-druginteractionsandefficientelimination,peptidesareidealagentstobeusedbyananesthesiologist.However,thenumberofpeptidesintheclinicgivenbyanesthesiologistsisunknown.Therefore,inadditiontopersonalexperience,weundertookaliteraturesearchtoidentifywhatpeptidesareapprovedbytheUSFDAandwhatpeptidescurrentlyinclinicaltrialshaveindicationsrelatedtoanesthesiologypractice.WeconductedaPubmedliteraturesearchusingaspecificpeptidenameandthewordanesthesia.Fromliteraturereviewandpersonalexperience,itisestimatedananesthesiologistuses14oftheapproximately26clinicallyapprovedpeptidesintheUS,or54%.Theseincludeagentssuchasoctreotide,bilvirudin,ziconotide,pitocin,vasopressin,nesiritideandeptifibatide.Peptidesinclinicaltrials,suchasdepelestatandlinaclotide,willalsobefrequentlyusedbyanesthesiologistsifapproved.Thesefindingssuggestanesthesiologistsarelikelytheprincipleadministratorsofpeptidesintheclinicandperhapsforpeptidesapprovedforfutureuse.Potentialreasonswhypeptidesarecommonlyusedamonganesthesiologistsandthebenefitsandproblems of clinical trials carried out by anesthesiologists will also be discussed.

P 13 Pharmacological Characterization of FE 203799, a Novel Long Acting Peptide Analog of Glucagon-like peptide-2 (GLP-2)DianeHargrove,SudarAlagarsamy,SteveQi,KarthikSrinivasan,GlennCroston, RegentLaporte,JavierSueiras-Diaz,KazimierzWisniewski,JenniferHartwig,HalinaWisniewski,MarkLu,AlexanderPosch,ClaudioSchteingart,PierreRivièreFerringResearchInstitute,4245SorrentoValleyBlvd.,SanDiego,CA92121

GLP-2isa33aminoacidpeptidethatisreleasedfromintestinalL-cellsfollowingnutrientingestionandactsatdistinctGproteincoupledGLP-2receptorsinthesmallintestineandcolontopotentlystimulateintestinalgrowth.GLP-2alsoincreasesnutrientabsorption,stimulatesmesentericbloodflowandmodulatesgastrointestinalmotility.GLP-2agonistsareefficaciousinanimalmodelsofdiseaseincludingmodelsoflargeandsmallbowelinflammation,shortbowelsyndromeandchemotherapy-andradiation-inducedmucositissuggestingtheymayhavetherapeuticpotentialforthetreatmentofgastrointestinaldiseasesanddisorders.ClinicaldevelopmentofGLP-2agonistsistestingthishypothesis.

Peptidesarewidelybelievedtohaverapidclearanceandashorthalf-life,limitingtheirclinicalutility.Indeed,nativeGLP-2hasashortcirculatinghalf-lifeduetocleavagebydipeptidylpeptidaseIV(DPP4)limitingitsdevelopmentasatherapeuticagent.ADPP4resistantanalogofGLP-2(teduglutide,h[Gly2]GLP-2(1-33))withsomewhatlowerclearancethanGLP-2isinclinicaltrials in patients with short bowel syndrome.

HereinwereportonthecharacterizationofFE203799,anovelGLP-2analogthatretainspotencyandselectivityatthehGLP-2receptorandhasagreatlyimprovedpharmacokinetic(PK)andpharmacodynamicprofile.Invitropotency(EC

50)atthe

hGLP-2receptorwasdeterminedusingHEK-293cellstransientlyco-transfectedwithhGLP-2receptorandacAMPresponsiveluciferase reporter plasmid. The EC

50valuesforFE203799,hGLP-2andteduglutidewere0.03,0.07and0.09nMrespectively.

InratPKstudies,FE203799wasshowntohavedramaticallylowerclearancethanGLP-2orteduglutide,resultinginalonghalf-life.Followingintravenous(IV)bolusadministration,theeliminationhalf-lifeofFE203799was8-and25-foldlongerthanteduglutideandhGLP-2respectively.Thehalf-lifeofFE203799wasevenlongerfollowingsubcutaneous(SC)administration.TreatmentwithFE203799resultedingreaterinvivopotencyandlessfrequentdosingtoachievepharmacodynamicefficacyforstimulationofintestinalgrowthinrats,likelystemmingfromtheobservedincreaseinhalf-life.

TheseuniquepropertiesofFE203799relativetoanalogscurrentlyinclinicaltrialsmayconferasuperiortherapeuticprofileforthe treatment of gastrointestinal diseases.

P 14 Novel T Cell Driven Approach Leads to the Identification of Immunoprevalent AntigensValeriaJudkowski1,RadleighG.Santos2,MarkK.Slifka3,DanielC.Douek4,BarneyS.Graham4,ClemenciaPinilla1*1TorreyPinesInstituteforMolecularStudies,SanDiego,CA92121,USA2TorreyPinesInstituteforMolecularStudies,PortSt.Lucie,FL34987,USA3VaccineandGeneTherapyInstitute,OregonHealth&ScienceUniversity,Beaverton,OR97006,USA4VaccineResearchCenter,NationalInstituteofAllergyandInfectiousDiseases(NIAID),NationalInstitutesofHealth(NIH),Bethesda,MD20892,USA

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The prevention and treatment of infectious diseases is highly dependent on the availability of reliable diagnostic tests and protectiveortherapeuticvaccines.Therealsoexistsanurgentneedtodevelopreliablebiomarkerstomonitortreatmentsuccess and to predict disease progression from asymptomatic to symptomatic disease in several disease scenarios. Theelucidationofthedisease-relevantantigensthatelicittheprotectiveimmuneresponsesiscriticalandrequiredforthe development of diagnostics and treatments. Here we present a novel “T cell driven approach” that permits the direct identificationofpathogenepitopesandproteinantigenscapableoftriggeringspecificTcellresponsesuponimmunizationinhumans.Thisapproachincludesasinglepathogeninvitrostimulation,thegenerationofpathogenspecificTcellclones,theevaluationoftheirspecificitybymultiplecytokineproduction,andthescreeningofthecloneswithpositionalscanningpeptidelibraries.PBMCfromsmallpoxvaccinateddonorswereusedtogeneratevacciniaspecificCD4+Tcellclones.ThepeptidespecificityoftheseTcellswaselucidatedinacompletelyunbiasedfashionbyscreeningeachofthecloneswithpositionalscanning libraries composed in total of trillions of peptides. Ten novel epitopes and their corresponding protein antigens from vacciniavirusthattriggerCD4+responsesuponsmallpoxvaccinationinhumanswereidentified.GM-CSF,whilenotastandardcytokineusedformonitoringTcellresponsesagainstvaccinesorinfections,wasfoundtorequirelowerantigenconcentrationforitsproductionthanothercytokines,suchasIFN-g,IL-2,andTNF-a.Furthermore,acomprehensiveanalysisofthereportedimmunogenicityofthevacciniaproteinsfromwhichtheidentifiedepitopesarederivedrevealedthatthe“Tcelldriven”approachpresentedhereresultsintheidentificationofpeptidesderivedfromhighlyimmunoprevalentvacciniaproteins.This“Tcelldriven”approachcanbereadilyimplementedtodeterminethespecificityoftheresponsefollowingvaccinationorinfectionwithlarge size pathogens for which other methodologies could be more cumbersome.

P 15 Development of Therapeutic Antibody Conjugates via Unnatural Amino Acid ChemistryStephanieA.Kazane,1BenjaminM.Hutchins,1ErikD.Wold,1JunY.Axup,1ChanHyukKim,1TsotneD.Javahishvili,3ShailajaSrinagesh,3MarkK.Shimazu,3SemsiEnsari,3VaughnV.Smider,2 and Peter G. Schultz1

¹DepartmentofChemistryandtheSkaggsInstituteforChemicalBiology 2DepartmentofMolecularBiology, TheScrippsResearchInstitute,LaJolla,CA92037 3Ambrx,LaJolla,CA92037

Immunoconjugatesandbispecificantibodiesareofconsiderableinterestinoncologybecauseoftheirabilitytotargettumorcellswithhighspecificitywhileleavinghealthytissueunharmed.Recombinantantibodiesandantibodyconjugatesarenowamajorclassoftherapeutics.TheFDAhasapprovedovertwentytherapeuticantibodies;however,therearestillsignificantdiscoveryandmanufacturingissuesduetoconjugationmethods.Theprimarygoalofmyresearchhopestoovercometheseobstaclesbyincorporatingsite-specificunnaturalaminoacids(UAAs)intotheconstantregionofantibodies.TheseUAAshavereactivityorthogonaltothetwentycanonicalaminoacidsandcanbeconjugatedeffectivelytodifferentmoieties(e.g.hydroxlamines)tocreategeometricallycontrolledbispecificantibodiesandimmunoconjugates.Wehavesite-specificallylabeledvariousantibodies(anti-Her2,anti-CD20,anti-CD3,etc.)withsingle-strandedDNAandPNA(peptidenucleicacids).This technique allows for control over both the valency and orientation of multivalent proteins by exploiting the sequence specificbasepairingofoligonucleotides.Librariesof“binder”(e.g.antibodies)and“effector”(e.g.toxins)moleculescanbeeasilygenerated,creatingacombinatoriallibraryofallpossiblemultivalentconjugatesthatcanthenberapidlyscreenedfortherapeutic agents.

P 16 A Novel Linker Technology to Improve Therapeutic Function of Lead PeptidesYusukeKohno¹,MikiMaeda¹,TakashiNakae¹,KazuhiroAoki²,KeiichiOhya²¹JitsuboCo.,Ltd.,KoganeiTokyo,Japan²TokyoMedical&DentalUniversity,Tokyo,Japan

WhilePEGylationiswellestablishedmethodtoenhanceitslifeinbody,itisachinglychallengingtoapplytopeptidedrugcandidates directly because it often loss primary therapeutic effect. This phenomenon is derived from the position where thefunctionalmoietyisappendedonthepeptides.Jitsuboestablishedanovellinkertechnologyavoidingsuchconcernsas to connect functional moiety into therapeutic sequences with conventional methods. This poster will show a new design peptides to inhibit osteoclast formation withPEGmodificationandoptimizedprocessesfromoriginalcyclicpeptidecontainingadisulfidebond.

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P 17 HT Screening for Bioactive Peptides that Increase Radiation Tolerance Using a Pooled Lentiviral Peptide Scanning LibraryAndreyKomarov,AlexChenchik,AndreiGudkov,MikhailMakhanov,VankateshNatarajanCellecta,Inc.MountainView,CA94043

Thereismuchinterestindevelopingtherapeuticsthatincreasetolerancetoradiationexposure.However,despitesignificanteffort,fewcompoundshaveyetbeenidentified.Toaddressthisneed,wehaveadoptedanovelapproachthatusesapooledlentiviralscanningpeptideexpressionlibrarytoscreenforpeptidesequencesthatstimulatetheNF-kBpathway,whichisthoughttoincreaseresistancetoionizingradiation.Thepeptideexpressionlibrary,designedfromallknownextracellularproteins,wasusedtotransduceanNF-kBreportercellline.CellsexpressingpeptideagoniststhatdemonstratemodulationoftheNF-kBpathwaywereisolatedbyFACSandthepeptidesequencesthenidentifiedbyhighthroughputsequencing.Subsequentvalidationofbothindividuallentiviralpeptideconstructsandchemically-synthesizedpeptidesconfirmedactivationofNF-kB,provingthattheapproachidentifiesactivity,notjustbinding.Invivotestingisunderwaytoevaluatetheextent that the individual peptides confer actual protection from radiation.

P 18 Demonstration of Anti-tumor Efficacy in Multiple Preclinical Cancer Models Using a Novel Peptide Inhibitor (Aurigene-012) of the PD1 Signaling PathwayPottayilGSasikumar,LeenaKSathyam,RajeevKShrimali,KrishnaprasadSubbarao,RaghuveerRamachandra,SureshkumarVadlamani,AmarnadhReddy,AswaniKumar,AdurthiSreenivas,SubbaReddy,SreevalsamGopinath,DoddaluriSSamiulla,MuraliRamachandraAurigeneDiscoveryTechnologiesLimited,39-40KIADBIndustrialAreaElectronicCityPhaseII,HosurRoad,Bangalore560100,India

Programmedcelldeath-1,animmunoreceptorbelongingtotheCD28family,playsanimportantroleinnegativelyregulatingimmuneresponses.BlockingofPD-1signallingpathwayhasbeenshowntoresultinrestorationofdefectiveimmunecellfunctionsincancerandchronicinfections.PD-1targetedtherapiesintheongoingclinicaltrialsarebasedoneitherantibodiesorfusionproteins.Toexploituniqueadvantagesofpeptidesoverantibodiesorfusionproteins,hereinwereportapeptidebasedstrategytoblockthePD1signalingpathway.Sequencescriticalforligand-receptorinteractionwereidentifiedandcombinedinanon-linearfashion.Thestrategyresultedinanovelpeptide,AUR-012(29mer),whichdisplayedsub-nanomolarpotencyindisruptionofPD1-PDL1/2interaction,andhighlyeffectiverestorationofproliferationandeffectorfunctionsofsplenocytesandPBMCs.InvivostudiesdemonstratedanexcellentPK-PDcorrelationwithsustainedPDfor>24h.Inpreclinicalmodelsofmelanoma,breastandkidneycancers,AUR-012showedsuperiorefficacycomparedtotherapeuticagentscurrentlyusedintheclinicininhibitionofbothprimarytumorgrowthandmetastasis.Interestingly,dosingonceinthreedayswasequallyefficaciousasonceadaydosingwithnosignsofoverttoxicityandgenerationofneutralizingactivity.ThesefindingssupportfurtherdevelopmentofAUR-012forpotentialclinicaluse.

P 19 Development of Non-opioid Dynorphin A Analogs Interacting with Bradykinin Receptors as an AntagonistYeonSunLeea,SaraM.Halla,DavidRankinb,BrianaPaiselyb,DhanaMuthua,JoseJ.Ortiza,FrankPorrecab,JosephinLaib,Victor J. Hrubya

aDepartmentofChemistry,TheUniversityofArizona,Tucson,AZ85721bDepartmentofPharmacology,TheUniversityofArizona,Tucson,AZ85721

Ithasbeenshownthatafternerveinjury,up-regulateddynorphindirectlyinteractswithbradykininreceptors(B1RandB2R)resultinginhyperalgesia,andHOE140,abradykinin2receptorantagonist,affordsantihyperalgesiceffectbyblockingtheinteraction between B2R and dynorphin.1,2Thisisanon-opioideffectthatcannotbeblockedbyopioidantagonists.Since[des-Tyr1]dynorphin(2-13)isknowntobindallostericallywiththeB2Rinthemicromolarrange,systematicstructure-activityrelationships study on the ligand was performed to identify the structural features for the receptor. The SAR results will be discussedindetail.SupportedbygrantsfromtheU.S.PublicHealthServices,NIH,andNIDA.

dynorphin A: H-Tyr--Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys--Trp-Asp-Asn-Gln-OH

[des-Tyr1]-Dyn A-(2-13)

1.J.Lai,MLuo,Q.Chen,S.Ma,L.R.Gardell,M.H.Ossipov,F.Porreca,NatureNeuroscience,2006,9,1534-1540.2.C.Altier,G.W.Zamponi,NatureNeuroscience,2006,9,1465-1467.

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P 20 BioHeatMap: Search, Visualize and Discover New Opportunities from the Scientific Literature RobertMeadowsBioheatmap Inc.

Atthecenterofthepharmaceuticalresearchers’literatureinterestistheworldwidebiomedicalscientificknowledgecoveredbyNIH’sPubMed™.Itamountstomorethan19millionarticlesandgrowsexponentially:Fromonemillionarticlesproducedinthe50s,tosevenmillionnewarticlesinthe00s.Overonemillionarticleswillbepublishedin2010intheover5,000coveredscientificjournals.Usingthisinformationeffectivelyistimeconsuming.ManyscientistshavetosplittheirtimebetweenlaboratoryendeavoursandliteratureanalysistofindexpertsandtosupportexistingandneweffortsAnindividualscientistmayspendasmuchas50%ofhis/hertimeatthecomputer,datamining,filteringandreadingPubMed™informationoneabstractatatime.Thisisanopportunitycostthatslowsdowntheresearchprocess,drivesupresearchcostsandwillcontinuetoburdenthepharmaceuticalindustryasdatasourcesbecomelargerandmoretopic-focused.

Wepresentaweb-basedsoftwaresuitedesignedtogivescientistsbothpanoramicandnarrowviewsofthescientificliterature.Withafewmouseclicksresearcherscanseedisease-substancerelationships,authorsandcentersofinterest,timelinesandactivity/intensitymetricsandmuchmore.Ourposterdescribesthesoftwareandillustratesitsutilitybyansweringthequestion:

AccordingtoPubmed™whoaretheprolificauthors,whataretheindications,whataretherelatedsubstances,whenwasitpopularandwherearethecentersofexcellenceforDesmopressin?

P 21 Reduction in Food Intake and Weight Loss in Dogs with UGP281, an Oral Anorexigenic Peptide NozerMehta,WilliamStern,AmySturmer,StevenCarl,VickiRay,AngeloConsalvo,ChristopherMeenan,ChristinaSisk,FrankRitacco,NancieSouders,SethPennington,JennaGiacchi,KarenVeintimilla,AustinVryhofandAliBolat.UnigeneLaboratories,Inc.,110LittleFallsRoad,Fairfield,NJ07004

Unigene’sleadpeptidedrug,UGP281,isproducedbyrecombinantexpressioninE.coliwithyieldsofapproximately500mg/Lofintact,extracellularsecretedpeptide.Anenteric-coatedcapsuleformulationfororaldeliveryofthispeptidehasbeen developed that includes excipients for the inhibition of intestinal proteases and enhancement of paracellular transport throughthelumenoftheintestine.ThephysiologicaleffectofUGP281onfoodintakeandbodymassinBeagledogs,hasbeeninvestigatedinplacebo-controlledstudiesusinginjectableorenteric-coatedcapsuleformulations.Inacrossoverdesignplacebocontrolledstudyovertwoweeks,dailyintramuscularinjectionsofUGP281ataconcentrationof5μg/kgresultedinareductioninfoodintakeof60to80%andaweightlossof6to8%.Inachronicoraldosingstudy,2groupsof4dogseachwerefastedovernightandgivenasingleoralcapsulecontainingeitherUGP281orplacebointhemorningandfedfor6hoursperday.Anacutereductioninfoodintakeandsustainedweightreductionof>8%comparedtoplacebowasobservedforaperiodof5weeks.Incomparativestudiesbyintramuscularinjectionsinaratmodel,UGP281demonstratesgreaterreductionsinfoodintakeandbodyweightthanotherpeptidedrugsinclinicaldevelopment.Basedontheresultstodate,UGP281offersthepotentialofapotent,patientfriendlyorallydosedpeptidetherapyforthemanagementofobesity.

P 22 Branched Peptide Inhibitors of Akt1StevenW.Millward¹,RyanK.Henning¹,GabrielA.Kwong²,SureshPitram³,HeatherD.Agnew³,KaycieM.Deyle¹,ArundhatiNag¹,JasonE.Hein5,SuSeongLee4,JaehongLim4,JessicaA.Pfeilsticker¹,K.BarrySharpless6,JamesR.Heath¹¹NanosystemsBiologyCancerCenter,DepartmentofChemistryandChemicalEngineering,TheCaliforniaInstituteofTechnology,PasadenaCA,91125²DivisionofHealthSciencesandTechnology,MassachusettsInstituteofTechnology,Cambridge,MA02139³IntegratedDiagnostics,CulverCity,CA902304 InstituteofBioengineeringandNanotechnology,TheNanos,Singapore1386695 SchoolofNaturalSciences,UniversityofCalifornia,Merced,CA953436 Dept.ofChemistry,TheSkaggsInstituteforChemicalBiology,TheScrippsResearchInstitute,LaJollaCA92037

TheAktkinaseisacriticalintracellularsignalingnodewhichgovernsmanypro-growth,anti-apoptoticpathways.ThetherapeuticefficacyofsmallmoleculeAktinhibitorsisoftencompromisedbypoorspecificity,afeaturecommontomostkinaseinhibitorsthattargetthehighlyconservedbindingpocketsthatdefinetheactivesite.Herewepresenttheuseofiterativeinsituclickchemistrytoassembleabranchedpeptidetriligandthatdisplayslow-micromolarinhibitorypotencyagainstAkt1whilebindingoutsidetheactivesite.Iterativeinsituclickchemistryutilizesthetargetproteintocatalyzetheazide-alkynecycloadditionreactionbetweenasolubleanchorpeptideandaresin-boundOBOCpeptidelibrary.Tocharacterizetheefficiencyoftheon-beadinsituclickreaction,wedevelopedanovelQPCR-basedstrategythatenabledthefirstquantitativeevaluationofits

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yieldrelativetothecopper-catalyzedprocess.Theseexperimentsalsodemonstratedtheeffectoftheproteintarget,ligandorientation,andlinkergeometryonreactionefficiency.Theresultingtriligandshowsmid-nanomolaraffinityandexcellentselectivityforAkt1andefficientlyimmunoprecipitatesfull-lengthAktfromOVCAR3ovariancancercelllysates.AfluorescentversionofthetriligandwasusedtolocalizeAktincellsstimulatedwithEGFandInsulindemonstratingitsutilityasatoolforcellbiologyandimmunocytochemistry.KineticsexperimentswereusedtoruleoutcompetitiveinhibitionwithrespecttotheATPandpeptidesubstrates,suggestinganovelallostericmechanismofinhibitionWearecurrentlyoptimizingtheinhibitorypotencyofthetriligandandexploringitsinvivoefficacyinmultiplecancercelllines.

P 23 Inhibition of Myelin-reactive T Cell Responses by a Small Molecule Peptide Mimetic HLA-DR2 Inhibitor for the Treatment of MSThomas Forsthuber1,NiannianJi1,ChristopherSelf2,NeilHayward3,andGaryL.Olson*2

1UniversityofTexasatSanAntonio,SanAntonioTX78249;2ProvidPharmaceuticalsInc.,9DeerParkDrive,MonmouthJunction,NJ08852USA;3DaiamedLLC,Cambridge,MA.

PV-267isanovel,highlyspecificsmallmoleculeinhibitorofantigenbindingtotheMS-associatedMHCclassIImoleculeHLA-DR2.Thepeptidemimeticcompoundisstabilizedtowardcathepsindegradativeenzymesfoundinantigenpresentingcellsandisalsofullystableinplasma.PV-267ishighlyefficaciousinthepreventionandtreatmentofEAEinHLA-DR2transgenicmice.Importantly,thecompoundishighlyeffectiveininhibitingtheproductionofproinflammatorycytokinesbymyelin-specificTcellsfromHLA-DR2+MSpatients.Exploratorypharmacokinetics,toxicology,formulation,andsynthesisstudiessupporttheselectionofPV-267fordevelopmentasatherapeuticforMS

TheworkhasbeenpartiallysupportedbyanNIHSBIRgrant(1R43NS048731-01),bytheNJEconomicDevelopmentAuthority,andbyFastForwardLLC,theinvestmentarmoftheNationalMultipleSclerosisSociety.

P24 Discovery of Bi-Functional Peptides Balanced in Glucagon Antagonism & GLP-1 Agonism Chenguang Ouyang1,BinYang2,PengyunLi1,VasilyGelfanov1,NickkiOttaway3, MatthiasH.Tschöp3,andRichardDiMarchi11IndianaUniversity,Bloomington,IN474012MarcadiaBiotech,Carmel,IN460323UniversityofCincinnati,Cincinnati,OH45237

GLP-1providesuniqueefficacyinthecontrolofbloodglucoseinthetreatmentofadult-onsetdiabetesbyenhancinginsulinandpartiallysuppressingglucagonsecretion.Itseemsplausiblethatadditionofglucagon-receptorantagonismtoselectiveGLP-1agonistswouldenhanceglucoselowering.Theidentificationofadual-actingpeptidefunctioningasanantagonistattheglucagonreceptorandanagonistattheGLP-1receptorconstitutesamolecularchallengeduetotheirstructuralhomology.Ourobservationsintothestructure-activity,startingwithglucagon/GLP-1co-agonistsdemonstratethatN-terminaltruncationtoyieldaspecificallyshortenedanalogfullyantagonizesglucagonactionwhilemaintainingfullGLP-1receptoragonism.Thechemicalrefinementoftheposition6aminoacidinadditiontobackbonesecondarystructurestabilizationbycovalentlactambondyieldedabalanceddual-actingpeptideindividuallycharacterizedinvitrotopossessanIC50attheglucagon-receptorandanEC50attheGLP-1receptorof20nM.Themixed-actionpeptide,whenadministeredinmice,exhibited both activities and lowered blood glucose. The molecular basis for differential activity at two homologous receptors constitutesaconundrumandsomethingworthyofstructuraldefinition.HomologyanalysisrevealedasetofputativeGLP-1receptor sites where mutations were introduced to identify the source of differential activity. The initial results indicate that the core domain in each receptor determines the pharmacology.

P 25 BMP-2 Derived Peptide Loaded Collagen Matrix For Bone Regeneration TherapyHyun-JungPark1,2,Jue-YeonLee1,Hyeon-JunIm1,Yoo-NaSeo1,Sang-ChulLee1,Mo-MiLee1,Yoon-JeongPark1,2,Chong-Pyoung Chung*1,3

1Researchcenter,NanoIntelligentBiomedicalEngineering(NIBEC)Corporation,Seoul,Korea,2Dentalregenerativebiotechnologymajor.SeoulNationalUniversity,SouthKorea3DepartmentofPeriodontology,SchoolofDentistry,SeoulNationalUniversity,Seoul,SouthKorea

Recombinant human bone morphogenetic protein stimulates regeneration of alveolar bone and cementum in periodontal defects. WehypothesizethatsyntheticpeptidederivedfromBMPreceptorIandreceptorIIbindingdomainsofBMP-2wouldhave bone regeneration activity. We chose collagen matrix as a supportive biomaterial for bone regeneration. Collagen is a biocompatibleproteinandmaintainsstructureofbone.Herein,collagenmatrixwasfabricatedandmodifiedwithsyntheticpeptidederivedfromBMP-2inordertoincreaseboneregeneration.

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Syntheticpeptidewassynthesizedandloadedintothecollagenmatrix.CellattachmentandproliferationonthemodifiedcollagenmatrixwasexaminedbyMTTassay,scanningelectronmicroscopy,andconfocalmicroscopy.OsteoblasticdifferentiationwasassessedbyALPaseactivity,AlizarinRedS,Calceinstaining.Expressionoffunctionalgenesandactivationofcellsignalingwereassessedbyreversetranscription-polymerasechainreactionandWesternblot.Inthisstudy,BMP-2derivedpeptidemodifiedcollagenmatrixpromotedosteogenicdifferentiationinamannersimilartoBMP-2.TheseresultsdemonstratedthatthepeptidederivedfromBMP-2loadedcollagenmatrixcanbeappliedasabioactivematerialfor bone regeneration therapy.

P 26 Peptide-Fibrin Matrix as a Tissue Engineering ScaffoldYoungSukChoi1*,JueYeonLee3,SeungJinLee2,ChongPyoungChung3,YoonJeongPark11 Dentalregenerativebiotechnologymajor.SeoulNationalUniversity,SouthKorea2 DepartmentofIndustrialPharmacy,CollegeofPharmacy,EwhaWomansUniversity,Seoul,Korea3 ResearchInstitute,NanoIntellegentBiomedicalEngineeringCorporation(NIBEC),JinCheon,Korea

Fibrinmatrixexploitsthefinalstageofthecoagulationcascadeinwhichfibrinogenmoleculesarecleavedbythrombin,convertintofibrinmonomersandassembledintofibrils,eventuallyformingfibersinathree-dimensionalnetwork.Inthepresentstudy,wedeterminedtheinvitrooptimalfibrinbindingpeptideforHaCaTcellsproliferationinfibrinmatrix.Allfibronectinderived(FND)peptidesweremanuallysynthesizedbytheF-mocchemistry.Thepresentstudyhasassessedasimplifiedversionofafibrinclotpreparedbyusingsolutionscontainingfibrinogen,fibronectinderivedpeptides,thrombin,calciumandaprotinin.ThedirectbindingkineticsofFNDpeptidestofibronectinwasexaminedusingSPR.Fibrinstructurecanbedeterminedmicroscopically,usingatomicforcemicroscope,scanningelectronmicroscopyorthermogravimetry.Inthisstudy,wereportthatFNDpeptidesincorporatedintoafibrinclotpromotescellspreadingandcytoskeletalorganizationthatisverydifferentfromthatseenonfibrinalone.ThenoveltyofthemanuscriptisbasedonthefunctionalizedsystembymixingFNDpeptidesspecificallytothefibrinscaffold matrix to provide signal and scaffold functions for tissue regeneration.

P 27 Use of a Positional Scanning Tetrapeptide Library to Discover Ligands that Restore Function at a Human Melancortin-4 Receptor PolymorphismEricaM.Haslach1,HuisoHuang1,MarcGuilianotti2,JonAppel2*,GinamarieDebevec2,PhaedraGeer2,RichardHoughten2,CarrieHaskell-Luevano1 and Clemencia Pinilla2 1DepartmentofPharmacodynamics,UniversityofFlorida2TorreyPinesInstituteforMolecularStudies,PortSt.Lucie,FL,*SanDiego,CA

TheL106Pmelanocortin-4receptorSNPhasbeenreportedasaheterozygouspolymorphisminanobesepatient.1 Endogenous melanocortinagonistshavedecreasedaffinityatL106P,whiletetrapeptideswereshowntoexhibitpotentactivity2. This mutation is located in the putative binding region for ligands and may be distorted due to the amino acid change. The screening and deconvolution of a positional scanning tetrapeptide library3composedofL,Dandunnaturalaminoacidsthatintotalrepresentsmorethan14milliontetrapeptidesresultedintheidentificationoftetrapeptidesthatrestorefunctionalactivity.Wefoundthattheincorporationof(pI)-D-Pheatposition2and(pNO2)-D-Pheatposition4exhibitednMpotencyattheL106PhMC4R.Thisstudydemonstratestheutilityofpositionalscanninglibrariesfortheidentificationofcompoundsthatcanrestorefunctionatnaturalhuman polymorphisms in obese patients.

ThisworkissupportedbyNIHgrantRO1DK64250(U.Florida)andtheStateofFlorida,ExecutiveOfficeroftheGovernor’sOfficeofTourism,TradeandEconomicDevelopment(TPIMS).1.Yeo,G.,Lank,E.J.,Farooqi,I.S.,etal.HumanMol.Genet.,2003,12,561-574.2.Xiang,Z,Literland,S.A.,Sorensen,N.B.,etal.Biochemistry,2006,45,7277-7288.3.Dooley,C.T.,Ny,P.,Bidlack,J.M.,andHoughten,R.A.,J.Biol.Chem.,1998,273,18848–18856

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P 28 Bioanalysis and Pharmacokinetics Profile of FE 203799: A Novel Glucagon-Like Peptide-2 (GLP-2) Long Acting Peptide AgonistSteveQi,KarthikSrinivasan,DianeHargrove,JenniferHartwig,SudarAlagarsamy,GlennCroston,RegentLaporte,JavierSueiras-Diaz,KazimierzWisniewski,HalinaWisniewska,MarkLu,AlexanderPosch,ClaudioSchteingart,PierreRivièreFerringResearchInstitute,4245SorrentoValleyBlvd.,SanDiego,CA92121

GLP-2isa33-aminoacidpeptidethatisreleasedfromintestinalL-cellsfollowingnutrient-ingestion.Itisknowntostimulateintestinalgrowth,nutrientabsorptionandmesentericblood-flowandtomodulategastrointestinalmotility.NativeGLP-2hasashorteliminationhalf-life(6.4and7.2mininratsandhumans,respectively)andhighclearance(24.6and6.8ml/min/kginratsandhumans,respectively)dueinparttoitssusceptibilityforthedipeptidylpeptidase-IV(DPP4)enzyme.ADPP4resistantanalogofGLP-2,teduglutide,hasalower,butstillrelativelyhigh,clearance(9.9and2ml/min/kginratsandhumans,respectively)thanGLP-2.Herein,wedescribeanovelGLP-2analog,FE203799,whichretainspotencyandselectivityatthehGLP-2receptorbuthasasuperiorADME/pharmacologicalprofile.

ThenovelGLP-2analogueFE203799wasfoundtobeequipotenttohGLP-2andteduglutideinaninvitrofunctionalassay.Inrats,FE203799wasshowntohavedramaticallylowerclearance(0.27ml/kg/min)thanGLP-2orteduglutide.ThePPBofFE203799wasfoundtobe99.7%,whichmaybethemainreasonforitslowsystemicclearance.FollowingIV-bolusadministration,theeliminationhalf-lifeofFE203799(159min)was8-and25-foldlongerthanteduglutideandhGLP-2,respectively.TheSChalf-lifeofFE203799wasevenlonger(701min,bioavailabilityof74%),suggestingratelimitingSCabsorption.ThePKparametersofFE203799obtainedinthevariousspeciesgivesinsightstoattempttopredictitsPKinhumans. Treatment with FE 203799 in rats resulted in greater in vivo potency and less frequent dosing when compared to teduglutide,likelyduetoitslongerhalf-life.TheseuniquepropertiesofFE203799may,in-turn,conferasuperiortherapeuticprofileinthetreatmentofgastrointestinaldisease.

P 29 Novel Selective Peptide Regulator of Protein Kinase C Based on Rational Approach DesignNirQvit,Marie-HeleneDisatnik,DAriaMochly-RosenStanfordUniversity,PaloAlto,CA

ProteinkinaseC(PKC)playsacriticalroleinvariousdiseasessuchascancerandstroke,andisakeyplayerinavarietyofsignaltransductionpathwayssuchasapoptosisandcellproliferation.PKCisalargefamilyofserine/threoninekinasesthattranslocatefromonecellcompartmenttoanotherfollowingactivation.Basedonanumberofrationalapproaches,shortpeptidesweredevelopedtoregulatePKCisozymeinteraction.ψPDK,apeptidethatderivedfromthePKCC2domain,wasdesignedtoaffectprotein-proteininteractionsthatareuniqueforpathologicalconditionsandnototherfunctions.Anex-vivomodelofischemiaandreperfusion(I/R)injuryshowedthatψPDKisdeltaPKC-specificregulatorthatselectivelyinducesdeltaPKCinteractionwithdistinctsubstratesinthemitochondria.AfterI/R(eventthatoccurduringheartattack)delta-PKCtranslocatestothemitochondriaintheheart.Wehavepreviouslyshownthatdelta-PKCactivationincreasescardiacdamagethroughthephosphorylationofpyruvatedehydrogenasekinase(PDK)andconsequentphosphorylationofmitochondrialenzymepyruvatedehydrogenase(PDH),resultsinadecreaseinATPregeneration.WefoundthattheψPDKpeptideinhibitspecificallytheinteractionofdelta-PKCwithPDK,whichleadtocardiacprotectionfollowingI/R.Sincethereareknownmorethan60differentproteinsthatcontainaC2domain,manyofwhicharesignalingproteins,wesuggestthatourapproachcanbeusedtogenerateuniquepharmacologicaltoolstostudytheseproteinsandperhapsalso,foridentifyingnewdrugforimportanthuman diseases.

P 30 Predictable and Tunable Drug Release From Macro-molecular Conjugates EricLSchneider,JeffCHenise,LouiseRobinson,RalphReid,GaryWAshley,DanielVSanti ProlynxLLC,26138ResearchRd.,Hayward,CA94545

ProLynxhasdevelopedanewformatforreleasablemacromolecule-drugconjugatesthatdoesnotrequireenzymehydrolysis,ishighlytunable,andgivespredictablecleavageratesbothin vitro and in vivo.Thetechnologyusesnovellinkersthatundergoß-eliminationreactionsatpre-programmedratestoreleasenativepeptides,proteinsandsmallmoleculedrugsfromconjugates,e.g.thoseusingpolyethyleneglycolascarrier.Asetofmodularlinkersisdescribedhavingasuccinimidylcarbonategroupforattachmenttoanamine-containingdrugorprodrug,anazidogroupforconjugationtoamacromolecularcarrier,andatunablemodulatorgroupthatcontrolstherateofß-eliminativecleavagebycontrollingtheacidityofanadjacentionizable hydrogen. Variation in the structure of the modulator translates into variation in the rate of drug elimination as describedbyalinearfreeenergyrelationship.Theselinkersareshowntoprovidepredictable,tunablereleaseratesofdrugsfrommacromolecularconjugatesoverarangespanninghourstomonthsatphysiologicalpH.?Thein vitro cleavage rates show excellent correlation with in vivorates.Theselinkersareexpectedtofindusewithbothcirculatingandnon-circulatingconjugates.

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P 31 Native Chemical Ligation Derived Method for Peptide/Protein C-terminal Amidation Chengzao Sun,GaryLuo,SwethaNeravetla,SoumitraGhoshandBruceForoodAmylinPharmaceuticals,Inc.SanDiego,CA92121

ManypeptideorproteintherapeuticsexistasC-terminalamidesfortheirbiologicalactivityandforstability.Whileshortpeptidescanbemadebysolidphasesynthesis,theneedremainsforprocessesthatcanproducelongpeptide/proteinamidesusingcost-effectiverecombinantprocedurescoupledwithpost-translationalamidation.

EnzymaticaswellaschemicalmethodshavebeendevelopedforC-terminalamidation,mostofwhichhavelimitationssuchaslowconversionrate,specificsequencerequirements,specialpurificationrequirementsorenzymeaccessibility.Wehavedevelopedachemicalamidationmethodthatconvertspeptide/proteinthioesterintocorrespondingc-terminalamides.Withthismethod,peptide/proteinthioesteristreatedwitha2-aminomercaptoethanolauxiliaryinanativechemicalligation(NCL)reactiontoformanintermediate,whichuponremovaloftheauxiliarywithTFAyieldsthepeptide/proteinamide.Wesuccessfullyconvertedtwosyntheticpeptidethioesters(DavalintideandPYY[3-36])topeptideamideswithhighconversionratesforvalidation of the methodology. Preliminary results of converting a recombinant peptide thioester to its amide form will also be reported.

Webelievethismethodcanbeapplicabletomostpeptides/proteinsasitinvolvesmildnativechemicalligationconditionandaTFA treatment step widely used in solid phase synthesis of peptides.

P 32 In-silico Tools for Drug Discovery: Protein Building Blocks, Peptide Design and the FoldX Energy Force FieldErikVerschueren¹*,Peter Vanhee¹*,FrancoisStricher¹,FredericRousseau²,JoostSchymkowitz²,LuisSerrano¹*Theseauthorscontributedequallytothiswork.¹EMBL-CRGSystemsBiologyUnit,CenterofGenomicRegulation,BarcelonaSpain²VIBSWITCHlaboratory,Dept.MolecularCellBiology,KULeuven,Leuven,Belgium

WewillpresentBriX(http://brix.crg.es),avastcollectionofstructuralproteinfragments(4-14residueslong),gatheredfromover7000non-homologousproteinsandclassifiedaccordingtostructuralsimilarity.Thesefragmentsaccuratelydescribe“proteinspace”withsub-angstromresolutionandcanbeusedforproteinmodelinganddesign.Wewillshowhowtheycanbeusedforthemodelingofproteinloops,variablepartsoftheproteinstructurethatarenotoriouslyhardtopredict.WhencombinedwiththeFoldXforcefield,weshowhowthesefragmentsandtheirlocalinteractionscanbeusedtopredictthestructureofprotein-targetingpeptides,andhowthiscanbeappliedforthenoveldiscoveryofpeptides.

ReferencesI. Vanhee P,VerschuerenE,BaetenL,StricherF,SerranoL,RousseauF,SchymkowitzJ:BriX:adatabaseofproteinbuildingblocksforstructuralanalysis,modelinganddesign.NucleicAcidsResearch2010,39:D435-D442.2.VanheeP,ReumersJ,StricherF,BaetenL,SerranoL,SchymkowitzJ,RousseauF:PepX:astructuraldatabaseofnon-redundantprotein-peptidecomplexes.NucleicAcidsResearch2009,38:D545-D551.3.VanheeP,derSlootvanAM,VerschuerenE,SerranoL,RousseauF,SchymkowitzJ:Computationaldesignofpeptideligands.TrendsinBiotechnology2011,doi:I0.1016/j.tibtech.2011.01.004.4.VanheeP,StricherF,BaetenL,VerschuerenE,LenaertsT,SerranoL,RousseauF,SchymkowitzJ:Protein-PeptideInteractionsAdopttheSameStructuralMotifsasMonomericProteinFolds.Structure/FoldingandDesign2009,17:1128-1136.5.VerschuerenE,VanheeP,derSlootvanAM,SerranoL,RousseauF,SchymkowitzJ:Proteindesignwithfragmentdatabases.CurrentOpinioninStructuralBiology2011,21:452-459.

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Notes 6th Annual Peptide Therapeutics Symposium

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