julie a. johnson, pharm.d. - university of florida
TRANSCRIPT
JULIE A. JOHNSON, PHARM.D.
Dean and Distinguished Professor
FROM THE DEAN
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It is my pleasure to welcome you to the 2019 University of Florida Drug Discovery Symposium. This two-day
symposium — hosted by the UF College of Pharmacy’s Center for Natural Products, Drug Discovery and
Development, or CNPD3, — serves as a unique opportunity for drug discovery experts from across Florida to share
their knowledge in the ever-advancing field of drug therapy.
We are excited during this, the third iteration of the symposium, to have Ben Shen, Ph.D., a professor and the director
of The Natural Products Library Initiative at Scripps Research, deliver the keynote address. His presentation titled,
“Challenges and Opportunities for Natural Products and Drug Discovery in the Genomic Era,” will link two UF College
of Pharmacy priorities: drug discovery and precision medicine. I hope you enjoy Dr. Shen’s remarks, as well as those
of our plenary speakers, Dr. John MacMillan from the University of California, Santa Cruz; Dr. Marvin Miller from the
University of Notre Dame and Dr. Paul Kenney from the Icahn School of Medicine at Mount Sinai.
Your attendance and participation demonstrate your commitment to drive forward preclinical and clinical drug
development. On behalf of the UF College of Pharmacy and the university at large, we are excited to host you in
Gainesville over the next two days. We hope you leave the conference ready to collaborate and contribute to drug
discovery and development.
Julie A. Johnson, Pharm.D.
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FROM THE CNPD3 DIRECTOR HENDRIK LUESCH, PH.D.Professor and Chair, Department of Medicinal Chemistry
Debbie and Sylvia DeSantis Chair in Natural Products Drug Discovery and Development
Director of Center for Natural Products, Drug Discovery and Development (CNPD3)
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It is my great pleasure to welcome you to our 3rd UF Drug Discovery Symposium hosted by the Center for Natural Products, Drug Discovery and Development (CNPD3). It has become a much-anticipated event since its inception in April 2016. The record number of over 170 registrants this year is an indication that this forum attracts scientists from across Florida to
share exciting new discoveries and promote interaction with UF colleagues. I am grateful to our internal and external speakers who are outstanding leaders in drug discovery and development (D3), for accepting our invitation to participate and share their expertise with the rising new stars of the D3 initiative at UF.
Highlights include world renowned plenary speakers at the forefront of innovative science in drug discovery, featuring our keynote speaker Ben Shen from Scripps Research, Florida, and three plenary speakers John MacMillan from the University of California, Santa Cruz, Marvin Miller from the University of Notre Dame, Indiana, and Paul Kenny from the Icahn School of Medicine at Mt. Sinai, New York. The sessions cover a range of topics from microbial genome mining, innovative screening to discovery, development and translational research. The symposium also emphasizes that natural products as genetically-encoded small molecules are exquisite starting points for drug discovery and development for cancer, infectious diseases, as well as drug abuse and pain, complementing synthetic small molecule approaches. Last but not least, special topic speaker Christian Jobin from the University of Florida will provide us with the latest insights into the gut microbiota as a crucial barometer in human health and disease and an emerging drug target.
This year’s event will also feature a special session for rising research-track faculty in addition to the popular graduate student and postdoc sessions. The top abstracts have been selected for short talks to complement a poster session. The best presentations of the next generation of drug discoverers will receive awards at the end of the symposium.
I believe the symposium promises to be electrifying and will reinforce that Florida is a powerhouse in drug discovery. Thank you for your participation and enjoy the event!
Hendrik Luesch, Ph.D.
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THURSDAY 25TH APRIL
7.15 am – 8.25 am REGISTRATION & BREAKFAST (Continental breakfast will be served; Posters will be set up)
8.30 am – 8.55 am Welcome Address and Introductory Remarks: Hendrik Luesch, Director, Center for Natural Products Drug Discovery and Development (CNPD3) Maureen Keller-Wood, Associate Dean for Research and Graduate Education, UF College of Pharmacy Jonathan Licht, Director, UF Health Cancer Center (UFHCC)
8.55 am – 9.40 am KEYNOTE ADDRESS: Challenges and Opportunities for Natural Products and Drug Discovery in the Genomic Era Ben Shen, Professor, Director, Natural Products Library Initiative, Scripps Research, Jupiter, FL
SESSION 1
9.40 am – 12.00 noon FROM GENOMES TO NATURAL PRODUCTS (Moderators: Valerie Paul & Amy Wright)
9.40 am – 10.05 am Synthetic Biology Approaches for Translating Microbial Genomes into Chemicals Yousong Ding, Assistant Professor, Department of Medicinal Chemistry, University of Florida, Gainesville, FL
10.05 am – 10.30 am Structure and Mechanism of the Biosynthesis Pathway to Microbiome-Produced, Genotoxic Colibactins Steve Bruner, Professor, Department of Chemistry, University of Florida, Gainesville, FL
10.30 am – 10.45 am COFFEE BREAK (Refreshments will be served)
10.45 am – 11.10 am Discovery of the Tiancilactone Antibiotics by Genome Mining of Atypical Bacterial Type II Diterpene Synthases Jeffrey Rudolf, Assistant Professor, Department of Chemistry, University of Florida, Gainesville, FL
UF DRUG DISCOVERY SYMPOSIUM2019 AGENDA
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11.10 am – 11.35 am Discovery of Novel Bacterial Queuine Synthesis and Salvage Enzymes by Comparative Genomics Valerie de Crécy-Lagard, Professor, Department of Microbiology and Cell Science, University of Florida, Gainesville, FL
11.35 am – 12.00 noon Harnessing Natural Product Biosynthetic Pathways from Actinomycetes Amy Lane, Associate Professor, Department of Chemistry, University of North Florida, Jacksonville, FL
12.00 noon – 12.55 pm LUNCH (Open Buffet)
PLENARY 1
1.00 pm – 1.45 pm Discovery of Selective Non-Small Cell Lung Cancer Toxins John MacMillan, Professor, Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA
SESSION 2
1.45 pm – 5.45 pm CANCER DRUG DISCOVERY AND TRANSLATION (Moderators: Chris Xing & Chenglong Li)
1.45 pm – 2.10 pm Structurally Defined Fluorogenic Probe Enables High-Throughput Screening of Inhibitors for Heparanase Lina Cui, Assistant Professor, Department of Medicinal Chemistry, University of Florida, Gainesville, FL
2.10 pm – 2.35 pm Combining Experimental and Computational Systems Pharmacological Approaches to Dissect Anti-Cancer Drugs Effects and Associated Toxicities Sihem Bihorel, Assistant Professor, Department of Pharmaceutics, University of Florida, Orlando, FL
2.35 pm – 3.00 pm Targeting Polyamine Metabolism in Pancreatic Cancers Otto Phanstiel, Professor, Department of Medical Education, University of Central Florida, Orlando, FL
3.00 pm – 3.10 pm COFFEE BREAK (Refreshments will be served)
3.10 pm – 3.35 pm Discovery of PROTAC Bcl-xL Degraders Guangrong Zheng, Associate Professor, Department of Medicinal Chemistry, University of Florida, Gainesville, FL
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3.35 pm – 4.00 pm Bcl-xl Proteolysis Targeting Chimeras are Potent Senolytic and Better Anti-cancer Agents Daohong Zhou, Professor, Department of Pharmacodynamics, University of Florida, Gainesville, FL
4.00 pm – 4.25 pm Covalent Inhibitors of ER Stress Response: Cancer Can’t Cope Juan Del Valle, Associate Professor, Department of Chemistry, University of South Florida, Tampa, FL
4.30 pm – 4.55 pm On the Trail of a Killer of Metastatic Breast Cancer Brian Law, Associate Professor, Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL
4.55 pm – 5.20 pm Genomic Approaches to Identify Markers Predictive of Response and Novel Targets in AML Jatinder Lamba, Associate Professor, Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL
5.20 pm – 5.45 pm Screening for Novel Compounds and Discovering New Targets in Acute Myeloid Leukemia Christopher Cogle, Professor, Department of Medicine, University of Florida, Gainesville, FL
5.45 pm – 7.15 pm POSTER SESSION (Drinks and light refreshments will be available)
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FRIDAY 26TH APRIL
7.15 am – 8.15 am BREAKFAST (Continental breakfast will be served)
PLENARY 2
8.15 am – 9.00 am Synthetic Sideromycins: Hijacking Microbial Iron Transport for Development of Targeted Antibiotics Marvin Miller, Professor Emeritus, Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN
SESSION 3
9.00 am – 12.10 pm ANTIBIOTICS AND INFECTIOUS DISEASE: FROM DISCOVERY TO THE CLINIC (Moderator: Jim Leahy)
9.00 am – 9.25 am Phenazine Antibiotic Inspired Discovery of Bacterial Biofilm-Eradicating Agents Robert Huigens, Assistant Professor, Department of Medicinal Chemistry, University of Florida, Gainesville, FL
9.25 am – 9.50 am TB and not TB: Discovering New Drugs for Bad Bugs Kyle Rohde, Associate Professor, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL
9.50 am – 10.15 am The Search for Better Tuberculosis Treatments Charles Peloquin, Professor, Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL
10.15 am – 10.30 am COFFEE BREAK (Refreshments will be served)
10.30 am – 11.40 am GRADUATE RESEARCH PRESENTATIONS (PhD Students) (Moderator: Bill Baker)
11.40 am – 12.10 pm POSTGRADUATE RESEARCH PRESENTATIONS (Postdoctoral Fellows) (Moderator: Siobhan Malany)
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12.15 pm – 1.10 pm LUNCH (Salad and Sandwiches)
1.10 pm – 1.50 pm SHORT TALKS BY RISING RESEARCH-TRACK FACULTY (Moderator: Taimour Langaee)
Biosynthesis of the Potent Anti-Proliferative Agent Lasonolide A Guojun Wang, Assistant Research Professor, Harbor Branch Oceanographic Institute, Florida Atlantic University, Fort Pierce, FL
Identification of Marine Natural Products with Activities Against Cancer Using High Content Imaging Esther Guzman, Associate Research Professor, Harbor Branch Oceanographic Institute, Florida Atlantic University, Fort Pierce, FL
Assessment of Mu-Opioid and Alpha-Adrenergic Receptor Involvement in the Effects of Kratom (Mitragyna speciosa) Alkaloids in Rats Takato Hiranita, Research Assistant Professor, Department of Pharmacodynamics, University of Florida, Gainesville, FL
PLENARY 3
1.50 pm – 2.35 pm Development of Novel Therapeutics for Substance Use Disorders Paul Kenny, Professor, Department of Neuroscience, Icahn School of Medicine at Mt. Sinai, New York, NY
2.35 pm – 2.45 pm COFFEE BREAK (Refreshments will be served)
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SESSION 4
2.45 pm – 4.55 pm DRUG ABUSE AND PAIN (Moderators: Brandon Warren & Jenny Wilkerson)
2.45 pm – 3.10 pm Characterization of ADME Properties of Mitragynine, the Major Alkaloid of Mitragyna speciosa (Kratom) Abhisheak Sharma, Research Assistant Professor, Department of Pharmaceutics, University of Florida, Gainesville, FL
3.10 pm – 3.35 pm Kratom Alkaloids: In vitro and In vivo Pharmacological Mechanisms Lance McMahon, Professor, Department of Pharmacodynamics, University of Florida, Gainesville, FL
3.35 pm – 4.00 pm NOP-Related Agonists as a Treatment Option for Pain and Opioid Abuse in Non-Human Primates Holden Ko, Professor, Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC
4.05 pm – 4.30 pm The Diversity of Cyclic Tetrapeptides: Structure-Activity Relationship Lessons Learned for Safer Analgesics Jane Aldrich, Professor, Department of Medicinal Chemistry, University of Florida, Gainesville, FL
4.30 pm – 4.55 pm Refinement of Cyclic Tetrapeptide Multifunctional Opioid Agonist/Antagonists as Safer Analgesics and Treatments for Opioid Addiction Jay McLaughlin, Associate Professor, Department of Pharmacodynamics, University of Florida, Gainesville, FL
SPECIAL TOPIC
5.00 pm – 5.30 pm Intestinal Microbiota: The Barometer of Health and Disease Christian Jobin, Professor, Department of Medicine, University of Florida, Gainesville, FL
5.30 pm – 7.30 pm AWARD CEREMONY & RECEPTION
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Ben Shen, Ph.D. Professor, Department of Chemistry, Natural Products Library Initiative, Scripps Research, Jupiter, Florida
Born and raised in China, Dr. Shen received B.Sc. from Hangzhou University (1982), M.S. from the Chinese Academy of Sciences (under the late Prof. Chutsin Liu, 1984), Ph.D. from Oregon State University (under Prof. Steven J. Gould, 1990), all in chemistry, and carried out postdoctoral research in molecular biology and biochemistry at University of Wisconsin-Madison (under the late Prof. C. Richard Hutchinson, 1991-1995). Dr. Shen served as a faculty at the University of California, Davis (1995-2001) and University of Wisconsin-Madison (2001-2010) before joining The Scripps Research Institute (TSRI) in 2011. Currently, Dr. Shen is Professor of Chemistry and Molecular Medicine and serves as the Co-Chair of the Department of Chemistry and Director of the Natural Products Library Initiative at Scripps Research. Current research in the Shen Lab concerns chemistry, biochemistry, and genetics of natural product biosynthesis and engineering in actinomycetes and development of enabling technologies to mine actinomycetal genomes for natural products, and anticancer and anti-infective drug discovery. The Shen lab has authored >265 publications and 11 published patents.
» KEYNOTE SPEAKER
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Challenges and Opportunities for Natural Products and Drug Discovery in the Genomic Era
Natural products are among the best sources of drugs and drug leads, and serve as outstanding small molecule
probes for dissecting fundamental biological processes. Natural product biosynthesis continues to push the
frontier of modern chemistry, biochemistry, and molecular biology by revealing novel chemical reactions, complex
enzyme systems, and intricate regulatory mechanisms. The progress made in the last two decades in connecting
natural products to the genes that encode their biosynthesis has fundamentally changed the landscape of natural
products research and sparked the emergence of a suite of contemporary approaches to natural products discovery.
Synthetic biology has made it possible to produce designer natural products by rational metabolic pathway
engineering. Genome mining has allowed targeted discovery of natural product scaffolds by exploring the vast
biosynthesis repertoire found in Nature. Selected studies from our current efforts on the enediynes, the leinamycin
family of natural products, and the Natural Products Library at Scripps Research will be presented to highlight the
challenges and opportunities for natural products and drug discovery in the genomic era.
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Dr. John MacMillan is a Professor in the Department of Chemistry and Biochemistry at the University of California-Santa Cruz, where his research laboratory focuses on the discovery and characterization of biologically active molecules from microorganisms. This research has focused predominantly on the therapeutic areas of infectious disease and oncology, combining phenotypic screening, isolation and mechanism-of-action studies towards the discovery of more than 100 new natural products. His work in the area of oncology has yielded a first in-class inhibitor of Hypoxia Inducible Factor 2 (HIF-2) that is currently undergoing clinical trials for the treatment of renal cell carcinoma. The MacMillan labs work in the area of natural products’ mechanism of action has yield multiple approaches, such as FUSION, to look at the mechanism of natural products on a library scale. This work has led to establishment of the Center for High Functional Annotation of Natural Products (HIFAN), which is a multi-institutional center funded by the NIH to study the mechanisms of botanicals and natural products.
Dr. MacMillan holds a Ph.D. in Chemistry from the University of California, Davis and a B.S. in Chemistry from the University of Iowa. Prior to moving to the University of California, Santa Cruz he was a faculty at the University of Texas Southwestern Medical Center, where he was the Chilton/Bell Scholar in Biochemistry and the holder of the Martha Steiner Chair in Biomedical Sciences.
John MacMillan, Ph.D. Professor, Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA
» PLENARY SPEAKER
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Discovery of Selective Non-Small Cell Lung Cancer Toxins
Determination of the functional role and mechanism of action of natural products and botanicals is a complex
challenge. Profound advances in the functional annotation of the protein-coding elements of the human genome
have had a transformative impact on discovery science directed at the mechanistic basis of human disease. Taking
advantage of this wealth of information, we have developed a technology platform to investigate the mechanism
of action of entire natural product libraries and crude mixtures in the context of cancer cells. This strategy is based
on perturbations of cells with miRNA, siRNA and natural products to produce a FUnctional SIgnature of ONtology
(FUSION). Our work combines chemical, biochemical and bioinformatics driven approaches to the discovery and
characterization of natural products. In this presentation, I will focus on our efforts to identify natural products that
are sub-type selective toxins against non-small cell lung cancer, using the natural products ikarugamycin, piericidin
and discoipyyrole A.
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Marvin Miller, Ph.D. Professor Emeritus, Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN
Professor Miller received his B.S. in chemistry from North Dakota State University in 1971, his Ph.D. from Cornell University in 1976 and postdoctoral studies as a National Institutes of Health fellow in the Department of Chemistry at the University of California at Berkeley (1975-77). He joined the chemistry faculty at Notre Dame in 1977. He was promoted to Associate Professor in 1982, Full Professor in 1986 and the George & Winifred Clark Chair Professorship in 1996. He served as Chairman of the Department of Chemistry and Biochemistry 2003-2005. He is a co-founder of Hsiri Therapeutics.
The primary interests in Professor Miller’s laboratory are in synthetic and bioorganic chemistry. The Miller group has benefitted from dedicated efforts of more than 150 graduate students, postdocs and research associates, as well as numerous visiting scholars, undergraduates and collaborators throughout the world. Most attention has been directed toward the development of new methodology and its incorporation into the syntheses and study of biologically important compounds. Special emphasis is given to asymmetric syntheses and studies of hydroxamic acid containing microbial iron transport agents (siderophores), amino acids, peptides, β-lactam antibiotics and carbocyclic analogs of antifungal and anticancer nucleosides. Recent efforts have been directed toward the syntheses and study of siderophore-antibiotic conjugates in a program designed to develop iron transport-mediated drug delivery agents, including those with potential microbe-triggered release processes.
Research in the Miller group has been supported continuously since 1977 by the NIH, the pharmaceutical industry and Department of Defense, as well as through the generous support of benefactors.Professor Miller has a wonderfully supportive family. He and his wife, Patty (who also is a research collaborator and coworker) have four grown children and eleven grandchildren.
» PLENARY SPEAKER
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Synthetic Sideromycins: Hijacking Microbial Iron Transport for Development of Targeted Antibiotics
New or repurposed antibiotics are desperately needed since bacterial resistance has risen to essentially all of our
current antibiotics and few new antibiotics have been developed over the last several decades. A primary cause
of drug resistance is the overuse of antibiotics that can result in alteration of microbial permeability, alteration of
drug target binding sites, induction of enzymes that destroy antibiotics (ie., beta-lactamases) and even induction
of efflux mechanisms. A combination of chemical syntheses, microbiological and biochemical studies demonstrate
that the known critical dependence of iron assimilation by microbes for growth and virulence can be exploited
for the development of new approaches to antibiotic therapy. Iron recognition and active transport relies on the
biosyntheses and use of microbe-selective iron chelating compounds called siderophores. Our studies, and those
of others, demonstrate that conjugates of siderophores and analogs can be used for iron transport-mediated drug
delivery (“Trojan Horse” antibiotics or sideromycins).
Several examples will illustrate that this approach can generate microbe selective antibiotics. The scope and
limitations of this approach, especially related to “microbe adaptability” and development of resistance, siderophore
based molecular recognition requirements, appropriate linker and drug choices will be described.
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Paul Kenny, Ph.D. Professor, Department of Neuroscience, Drug Discovery Institute, Icahn School of Medicine at Mt. Sinai, New York, NY
Dr. Kenny is the Ward-Coleman Professor and Chairman of The Nash Department of Neuroscience and Director of the Drug Discovery Institute at the Icahn School of Medicine at Mount Sinai. Dr. Kenny is also co-founder of Eolas Therapeutics Inc., a company focused on developing novel medications for drug addiction. Dr. Kenny serves as a Senior Editor for The Journal of Neuroscience. Dr. Kenny is a graduate of Trinity College, Dublin, where he earned a degree in Biochemistry. He completed his Ph.D. in neuropharmacology at King’s College, London. Dr. Kenny completed his postdoctoral training at The Scripps Research Institute in La Jolla, CA. Prior to joining the Icahn School of Medicine at Mount Sinai, Dr. Kenny was a faculty at The Scripps Research Institute in Jupiter, Florida. Research in Dr. Kenny’s laboratory is focused on understanding the molecular neurobiology of drug addiction, obesity and schizophrenia. Dr. Kenny has received numerous awards for his research, including the Daniel H. Efron Research Award from the American College of Neuropsychopharmacology (ACNP), the Jacob P. Waletzky Memorial Award from the Society for Neuroscience (SfN), Distinguished Investigator Award from NARSAD, and the Tom Connor Distinguished Investigator Award from Neuroscience, Ireland.
» PLENARY SPEAKER
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Development of Novel Therapeutics for Substance Use Disorders
Orexin-1 receptors (OX1Rs) are known to regulate the motivation to seek and consume nicotine and other drugs
of abuse in laboratory rodents, but underlying mechanisms are unclear. Consistent with these previous findings,
we found that pharmacological disruption of OX1 receptor-mediated transmission, with well characterized tool
OX1R antagonists, decreased the motivation to consume nicotine, and attenuated reinstatement of extinguished
nicotine-seeking responses, in mice, rats and monkeys. These observations were corroborated by studies in OX1R
knock-out mice. Using OX1-R GFP mice and chemogenetic approaches we identified a population of previously
uncharacterized OX1 receptor-regulated neurons in a circumscribed region of dorsal thalamus. These cells exert
profound control over nicotine-seeking behaviors, but do not regulate reward-related actions of nicotine. Instead,
these OX1 receptor-expressing thalamic neurons regulate the “value” of the drug. These findings provide strong
rationale to develop OX1R antagonists to treat tobacco dependence and other drug addictions. To identify novel
OX1 receptor antagonists, CHO cells stably expressing OX1Rs or OX2Rs were generated and competition binding
assays and intracellular calcium responses used to screen molecules. We identified a series of novel OX1 receptor
antagonists with drug-like physiochemical properties. A lead molecule in this series has progressed through IND-
enabling toxicology studies in rat and dog and will be advanced to a Phase 1 human safety study. In summary, OX1
receptors regulate the motivational properties of nicotine through a novel thalamic circuit. Targeting this circuit using
selective OX1R antagonists represents a novel strategy to facilitate abstinence from the use of tobacco, opioids and
other abused drugs.
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Christian Jobin, Ph.D. Professor, Department of Medicine, University of Florida, Gainesville, FL
Dr. Christian Jobin is the Gatorade Trust Professor of Medicine at the University of Florida Gainesville. He is the co-leader of the Cancer Therapeutics Host Response research program at the University of Florida Health Cancer Center. He received his PhD in Immunology/Microbiology from Université Laval (Quebec, Canada) in 1994. He did a post-doctoral fellowship at the University of North Carolina Chapel Hill working on bacteria host interaction in the intestine. Dr. Jobin’s research focuses on establishing the functional impact of bacteria in inflammation and carcinogenesis and deciphering mechanism of action. Using genetically engineered mice and zebrafish, germ-free and gnotobiotic technology in combination with microbial genomics, his lab studies the role of bacteria in cancer. His laboratory showed the key role of genotoxic microbial gene clusters in the development of carcinogenesis. He demonstrated influences of inflammation on intestinal microbial carcinogenic activities. He has published over 160 scientific papers (Science, Nature, Nat. Comm., Nat. Micro., Immunity, J. Exp. Med., Gastroenterology) and presented his work at various national and international scientific meetings (>190 conferences). His research, supported by the National Institute of Health has led to numerous awards and honours (Mucosal Immunology Society Award, American Gastroenterological Association Fiterman Young Investigator Basic Research Award, UF Senior Faculty Excellence in Research Award). Dr. Jobin has served on several study sections including American Cancer Society, CCFA Fellowship and Career Awards, NIH tumor microenvironment and he is currently serving on the Gastrointestinal Mucosal Pathobiology study section (GMPB-permanent member).
» PLENARY SPEAKER
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Intestinal Microbiota: The Barometer of Health and Disease
Gene-environment interaction plays a key role in disease susceptibility including obesity, metabolic syndrome,
neurological disorders and cancer. Microbiota, an important environmental factor is directly influenced by known
disease risk factors such as lifestyle, diet and inflammation. In this lecture, I will present evidence that intestinal
microbiota could modify disease outcomes and treatment responses. This impact of intestinal microbiota on
host homeostasis operates through production of secondary metabolites or biotransformation of environmental
factors that impact host function. Understanding the far-reaching impact of microbiota on various pathologies
will likely identify new potential ways to promote host resilience and to design novel therapeutic avenues for
disease management.
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SESSION 1
SYNTHETIC BIOLOGY APPROACHES FOR TRANSLATING MICROBIAL GENOMES INTO CHEMICALS
Yousong Ding, Ph.D.Assistant Professor, Department of Medicinal Chemistry, University of Florida, Gainesville, FL
Natural products-based drug discovery has achieved tremendous successes, but the high rate of rediscovery and limited chemical supply are two major challenges the field is facing. On the other hand, recent advances of DNA sequencing techniques illuminate extraordinarily rich potential of microbial strains for drug discovery and development, of which we have only tapped the surface. Over the past five and half years, my research laboratory has focused on the translation of genomic data into valuable substances using synthetic biology approaches. In this talk, I will share our recent studies in this research direction. Specifically, I will discuss the production of bioactive cyclic dipeptides (aromatic diketopiperazines) and two different types of unnatural amino acids in synthetic biology chassis of three bacterial phyla. Furthermore, I will briefly describe the application of cell-free synthetic biology approaches to explore broader chemical space of natural products. Overall, our work suggests that synthetic biology
approaches enable the exploration of the promising potential of microbial genomes for basic and translational research.
STRUCTURE AND MECHANISM OF THE BIOSYNTHESIS PATHWAY TO MICROBIOME-PRODUCED, GENOTOXIC COLIBACTINS
Steve Bruner, Ph.D.Professor, Department of Chemistry, University of Florida, Gainesville, FL
The E. coli-derived genotoxic colibactin, encoded by a natural product PKS/NRPS gene cluster, enhances colonic tumor development in mice and the prevalence of the cluster is higher in colorectal cancer patients than normal controls. Limited characterization of the gene products and associated function has prevented fundamental knowledge on how this E. coli contributes to colorectal cancer, the active, mature structure of the natural product and genotoxic mechanism of action. We have employed a structural genomics approach, where protein structures of gene products with unassigned function are determined to provide unique insight. We have targeted gene products in the island that play distinct roles in the predicted biosynthesis and function of colibactin. These include an uncommon natural product transporter, ClbM; a self-resistance protein ClbS with novel enzyme chemistry and mechanism of action and a unique hydrolase, ClbL.
» SPEAKER ABSTRACTS
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DISCOVERY OF THE TIANCILACTONE ANTIBIOTICS BY GENOME MINING OF ATYPICAL BACTERIAL TYPE II DITERPENE SYNTHASES
Jeffrey Rudolf, Ph.D.Assistant Professor, Department of Chemistry, University of Florida, Gainesville, FL
The genomic era, with its ever-increasing amounts of sequence data, has brought about a rejuvenation in natural products discovery. While genome mining has significantly advanced the discovery and study of microbial natural products, particularly major families including the polyketides and nonribosomal peptides, the discovery of bacterial (di)terpenoids continues to lag behind. The discrepancy in numbers of diterpenoids found in plants and fungi vs bacteria, in spite of the fact that bacteria indeed possess the biosynthetic machinery for diterpenoid production, is striking. Here, we detail our discovery of the tiancilactone diterpenoid antibiotics by genome mining of type II diterpene synthases that do not possess the canonical DXDD motif. This work highlights the biosynthetic potential that bacteria possess to produce diterpenoids, features holistic genome mining techniques to prioritize gene clusters for discovery efforts, and provides inspiration for continued efforts in discovering diterpenoid natural products from bacteria.
DISCOVERY OF NOVEL BACTERIAL QUEUINE SYNTHESIS AND SALVAGE ENZYMES BY COMPARATIVE GENOMICS
Valerie de Crécy-Lagard, Ph.D.Professor, Department of Microbiology and Cell Science, University of Florida, Gainesville, FL
Identifying the function of every gene in all sequenced organisms is the major challenge of the post-genomic era and an obligate step for any systems biology approach. This objective is far from reached. By various estimates, at least 30-50% of the genes of any given organism are of unknown function, incorrectly annotated, or have only a generic annotation such as “ATPase”. Moreover, with ~10000 genomes sequenced and ~100,000 in the pipeline (http://www.genomeson.line.org), the numbers of unknown genes are increasing, and annotation errors are proliferating rapidly. For some gene families, 40% of the annotations are wrong. On the other side of the coin, there are still ~1,900 known enzyme activities for which no corresponding gene has been identified and these numbers are also increasing. This biochemical knowledge is yet to be captured in genome annotations.
Using mainly a comparative genomic approach, we have linked gene and function for around 50 families related mainly to the fields of coenzyme metabolism, tRNA modification, protein modification and more recently metabolite repair. This approach integrates several types of data and uses filters,
» SPEAKER ABSTRACTS
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sieves, and associations to make predictions that can then be tested experimentally. An unknown gene’s function may thus be predicted from those of its associates: the ‘guilt by association’ principle. Associations that can be derived from whole genome datasets include: gene clustering, gene fusion events, phylogenetic occurrence profiles or signatures and shared regulatory sites. Post-genomic experimental sources such as protein interaction networks, gene expression profiles and phenomics data can also be used to find associations. In practice it is often ‘guilt by multiple association’ as genes can be associated in several ways and analyzing more than one of these improves the accuracy of predictions.
We have applied these methods to decipher the synthesis and salvage pathways for a conserved deazapurine modifications of tRNA, Queuosine (Q). We will discuss our recent discoveries on novel queuosine salvage pathways in human pathogens, revealing that both microbes and host fight for this quasi-vitamin.
HARNESSING NATURAL PRODUCT BIOSYNTHETIC PATHWAYS FROM ACTINOMYCETES
Amy Lane, Ph.D.Associate Professor, Department of Chemistry, University of North Florida, Jacksonville, FL
Actinomycetes, a group of gram-positive bacteria, are renowned sources of structurally intriguing natural products that are assembled via unique biosynthetic
pathways. Characterization of these pathways facilitates the development of natural products as pharmaceuticals and agrochemicals, provides tools for chemoenzymatic syntheses, and offers insights into microbial ecology and evolution. My research program aims to harness the biosynthetic potential of actinomycetes from marine sediments. This presentation will highlight our findings for pathways in which cyclodipeptide synthases (CDPSs) catalyze 2,5-diketopiperazine (DKP) assembly from aminoacyl-tRNAs. Although CDPSs are broadly distributed across bacterial phyla, fewer than ten multistep biosynthetic pathways that include CDPSs have been experimentally characterized to date. The nocardioazine natural products are uniquely prenylated and methylated indole alkaloid DKPs, and nocardioazine A acts as a non-cytotoxic inhibitor of P-glycoprotein to reverse drug resistance of cancer cell lines. We unveiled the nocardioazine biosynthetic pathway from a marine actinomycete, demonstrating that a CDPS catalyzes cyclo(L-Trp-L-Trp) DKP precursor formation followed by tailoring of this DKP via an isomerase, prenyltransferase, and methyltransferase to yield nocardioazine B. The nocardioazine pathway was also applied as a model for development of a biosynthetic platform for generating DKPs from unnatural amino acids, extending the utility of CDPS as biocatalysts. Together, our results highlight Nature’s aptitude for chemical synthesis and showcase the utility of biosynthetic approaches for expanding the breadth of chemical space provided by natural products.
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SESSION 2
STRUCTURALLY DEFINED FLUOROGENIC PROBE ENABLES HIGH-THROUGHPUT SCREENING OF INHIBITORS FOR HEPARANASE
Lina Cui, Ph.D.Assistant Professor, Department of Medicinal Chemistry, University of Florida, Gainesville, FL
Heparanase, endo-β-D-glucuronidase, can cleave heparan sulfate (HS) side chains of heparan sulfate proteoglycans (HSPGs) to generate biologically active carbohydrate fragments, leading to extracellular matrix (ECM) remodeling/degradation and release of protein ligands. The expression of heparanase is significantly elevated in almost all cancer types, and increased heparanase activity is mostly linked with increased angiogenesis, metastasis, and shortened post-surgery survival. However, the search of effective heparanase inhibitors is hindered by the lack of efficient probes for heparanase activity. We have developed a set of structurally defined fluorogenic carbohydrate small molecules enabling high-throughput screening of inhibitors for heparanase.
COMBINING EXPERIMENTAL AND COMPUTATIONAL SYSTEMS PHARMACOLOGICAL APPROACHES TO DISSECT ANTI-CANCER DRUGS EFFECTS AND ASSOCIATED TOXICITIES
Sihem Bihorel, Ph.D.Assistant Professor, Department of Pharmaceutics, University of Florida, Orlando, FL
Quantitative systems pharmacology and toxicology (QSP/T) is a bourgeoning mathematical modeling field that seeks to better understand pathophysiology, pharmacological (efficacy) and toxicological (safety) mechanisms from the levels of molecular pathways (–omics), regulatory networks, cells, tissues, organs, and ultimately the whole organism on diseases such as cancer. A network-centric view of biology and the integration of mechanistic modeling and simulation with quantitative experimental studies are two central themes that help distinguish QSP/T as a comprehensive and multi-disciplinary endeavor.
As a result, computational methods for QSP/T analyses provide a powerful means for analyzing experimental findings, interpreting biological behaviors, testing hypotheses, and designing experiments by integrating large amounts of experimental data into mathematical models of regulatory networks and cell behavior. This presentation will explore a hierarchical modeling approach where a large mechanistic mathematical model provided a framework to integrate a
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wide variety of experimental data, from in vitro observations to clinical results and illustrate how QSP/T models are being used to gain a knowledge of cancer and anti-cancer drugs responses.
TARGETING POLYAMINE METABOLISM IN PANCREATIC CANCERS
Otto Phanstiel, Ph.D.Professor, Department of Medical Education, University of Central Florida, Orlando, FL
New approaches are needed for treating pancreatic cancers as patients diagnosed with this disease have a five year survival rate of only 8%. All cells contain polyamines, which are low molecular weight aliphatic amines. These simple molecules play diverse roles in cells ranging from translation, transcription, chromatin remodeling and immune response. While polyamine depletion has been known for a long time to slow the grow of cancer cells, few compounds have been developed which lead to sustained polyamine depletion. While polyamine biosynthesis inhibitors like difluoromethylornithine (DFMO) have been shown to slow cancer cell growth both in vitro and in vivo, this drug often has only a cytostatic effect. Moreover, tumors often escape this monotherapy via upregulated polyamine import to replenish their depleted polyamine pools. Thus, the development of polyamine transport inhibitors (PTIs) is warranted. This talk will discuss
our progress in developing new ways to provide sustained intracellular polyamine depletion via new PTI designs and the combination therapy of DFMO+PTI for the treatment of pancreatic cancers.
DISCOVERY OF PROTAC BCL-XL DEGRADERS
Guangrong Zheng, Ph.D.Associate Professor, Department of Medicinal Chemistry, University of Florida, Gainesville, FL
The anti-apoptotic protein Bcl-xL is a well validated cancer target. However, dose-limiting thrombocytopenia has limited the utility of Bcl-xL inhibitors, such as navitoclax (ABT-263), as cancer therapies. Thrombocytopenia is an on-target toxicity of Bcl-xL inhibitors because platelets depend on Bcl-xL for survival. To circumvent this dose-limiting toxicity, we have been using PROTAC approach to design small molecules that can recruit Bcl-xL protein to E3 ubiquitin ligases for induced degradation. Our hypothesis is that since PROTAC molecules rely on E3 ligases to induce protein degradation, and if the E3 ligases are minimally expressed in platelets, these PROTACs will have reduced platelet toxicity compared with their corresponding Bcl-xL inhibitors. In this presentation, I will discuss our proof-of-concept studies and progress in the discovery of highly potent and selective PROTAC Bcl-xL degraders.
» SPEAKER ABSTRACTS
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BCL-XL PROTEOLYSIS TARGETING CHIMERAS ARE POTENT SENOLYTIC AND BETTER ANTI-CANCER AGENTS
Daohong Zhou, Ph.D.Professor, Department of Pharmacodynamics, University of Florida, Gainesville, FL
BCL-XL is a well-validated target for senescent cells and cancer. However, the on-target and dose-limiting thrombocytopenia induced by BCL-XL inhibition prevents the use of BCL-XL inhibitors as safe and effective senolytic and antitumor agents. Here we report the development of the first cell-specific proteolysis targeting chimera (PROTAC) to overcome the on-target and dose-limiting platelet toxicity of ABT263, a dual BCL-2/BCL-XL inhibitor and a potent senolytic and anticancer drug with unrealized therapeutic potential. This is achieved by converting ABT263 into a BCL-XL PROTAC that targets BCL-XL to the cereblon (CRBN) or Von Hippel-Lindau (VHL) E3 ligase for ubiquitination and proteasome degradation.
We found that BCL-XL PROTACs are more cytotoxic to a variety of senescent cells and BCL-XL-dependent leukemia and cancer cells but significantly less toxic to normal cells and platelets in vitro than ABT263 because CRBN and VHL are poorly expressed in platelets. In vivo, BCL-XL PROTACs effectively clear senescent cells in normally aged mice and inhibits the growth of several xenograft tumors as a single agent or in combination with other BCL-2 family protein inhibitors or
conventional chemotherapeutic agents, without causing significant thrombocytopenia. These findings demonstrate the potential to use PROTAC technology to overcome on-target drug toxicities. Furthermore, BCL-XL PROTACs may be developed as the safe first-in-class BCL-XL targeting senolytic and antitumor agent.
COVALENT INHIBITORS OF ER STRESS RESPONSE: CANCER CAN’T COPE
Juan Del Valle, Ph.D.Associate Professor, Department of Chemistry, University of South Florida, Tampa, FL
The endoplasmic reticulum (ER) stress response is activated in response to various stimuli and is crucial for maintaining the fidelity of the cellular proteome. Gene copy number amplification and aberrant protein expression are established hallmarks of cancer and several malignancies have been shown to co-opt ER stress response mechanisms in order to cope with proteotoxic stress. Inositol-requiring enzyme 1 (IRE-1) is an ER stress sensor that governs expression of the functional transcription factor XBP-1s through a specific mRNA splicing event. Hyperactivated IRE-1 can thus rescue cells from apoptosis and restore homeostasis through regulation of ER-resident chaperones and components of the ER-associated degradation machinery. Building on the hypothesis that secretory B-cell cancers may rely on a robust ER stress
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response for survival, we initiated a campaign to target IRE-1 RNase activity with small molecules. Our efforts led to the discovery of tricyclic chromenone-based IRE-1 inhibitors that phenocopy XBP-1s depletion in vitro and in vivo.
Chemical optimization yielded a series of prodrugs with improved efficacy against chronic lymphocytic leukemia and graft-versus-host disease progression. Here, we also present insights into the mechanism-of-action for this class of inhibitors in the context of Myc-driven cancers and hematopoietic stem cell renewal. Further structural tailoring of lead compounds recently afforded stimuli-responsive analogs that enable spatiotemporal control of IRE-1 RNase activity in whole cells. Together, these studies validate IRE-1 as an attractive target in several models of cancer and pave the way for the development of drug candidates based on covalent inactivation of the IRE-1 RNase domain.
ON THE TRAIL OF A KILLER OF METASTATIC BREAST CANCER
Brian Law, Ph.D.Associate Professor, Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL
Despite improvements in detection and therapy, breast cancer remains the second leading cause of cancer death in women. An estimated 41,760 women will die of breast cancer
in 2019. Breast cancer mortality stems from tumor resistance to therapy and our inability to combat metastatic disease. Breast tumors that overexpress the HER2 tyrosine kinase are aggressive and frequently acquire drug resistance. About half of Triple-Negative Breast Cancers, which lack the therapeutic targets HER2, Estrogen Receptor, and Progesterone Receptor, overexpress the EGFR tyrosine kinase. Hence, agents that selectively kill EGFR+ and HER2+ tumors could increase the survival of patients with these highly aggressive malignancies. We identified a series of compounds termed Disulfide bond Disproportionation Agents (DDAs) that selectively kill cancer cells that overexpress EGFR or HER2.
DDAs induce Endoplasmic Reticulum (ER) stress in the context of EGFR or HER2 overexpression, but do not affect nontransformed cells or cancer cells with low EGFR/HER2 levels. DDAs cause dramatic tumor necrosis in animal models of human breast cancer without detectable toxicity. Context-dependent DDA induction of ER stress kills cancer cells by driving the upregulation, oligomerization, and activation of Death Receptor 5 (DR5) in the absence of its ligand TRAIL. DR5 activation by DDAs causes cell death through the Caspase 8-Caspase 3 cascade, and DDA-driven cell death is largely ablated by knocking out DR5. TRAIL has been considered a promising anticancer agent due to its high toxicity to cancer cells without affecting nontransformed cells or normal tissues. Unfortunately, tumors frequently acquire TRAIL resistance by downregulating DR5. Small molecules that directly upregulate
» SPEAKER ABSTRACTS
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and activate DR5 could be superior to TRAIL and other DR5 agonists in their anticancer efficacy, while exhibiting the impressive TRAIL safety profile.
DDAs selectively alter the pattern of disulfide bonding in the extracellular domain of DR5, resulting in its oligomerization and activation. Interestingly, the closely related TRAIL receptors DR4 and DR5 share the same patterns of disulfide bonding, but DDAs do not affect DR4 levels or activity. Thus, DDAs are unique among small molecules in their ability to selectively activate DR5 in EGFR or HER2-overexpressing cancer cells through a novel mechanism involving DR5 oligomerization and caspase-dependent apoptosis of tumor cells.
GENOMIC APPROACHES TO IDENTIFY MARKERS PREDICTIVE OF RESPONSE AND NOVEL TARGETS IN AML
Jatinder Lamba, Ph.D.Associate Professor, Department of Pharmacotherapy and Translational Research, University of Florida,Gainesville, FL
Acute Myeloid Leukemia (AML) has a dismal outcome with survival rates from <20% in elderly to 40-60% in young and pediatric patients. Despite the use of intensive chemotherapeutic regimens containing cytarabine, a mainstay of AML chemotherapy, in combination with stem cell transplantation, majority of the patients with AML relapse. This is primarily due to development of resistance
which remains a significant challenge in AML. It is difficult to predict which individuals will respond best to treatment and those who are at the most risk of relapse. There is thus an urgent unmet need to identify the genetic characteristics of an individual’s cancer that can help predict clinical outcome, guide the use of appropriate therapy as well as identify novel drug targets. Using a novel statistical method, PROMISE (PRojection Onto the Most Interesting Statistical Evidence), we have integrated transcriptomic and DNA methylation signatures to identify genes predictive of multiple clinical endpoints in AML. Notable genes exhibiting a detrimental pattern included PIK3C3, which is involved in the PI3K/PTEN/Akt/mTOR signaling cascade, AKR1C3, an aldo-keto reductase, implicated in myelopoiesis; UB2EV1, apoptosis inhibitor through NF-κ B activation and other genes of strong biological significance as NFkB1, NOTCH2, DCK, DERA, APOBEC3b, HMBOX1 GPR56, GPR97, MAPK14, E1F4B; DNA repair genes: DCLRE1C; transcription factors: YY1 and REPIN etc. We are currently pursuing CRISPRcas9 synthetic lethal screening integrated with patient data to create a robust AML response score predictive of treatment-outcome and identify patients with higher relapse-risk and enhance developing individualized and focused application of targeted therapies in leukemia. Our data simultaneously identifies new druggable targets that could be tested for development of novel-targeted agents or repurposing of already approved agents.
» SPEAKER ABSTRACTS
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SCREENING FOR NOVEL COMPOUNDS AND DISCOVERING NEW TARGETS IN ACUTE MYELOID LEUKEMIA
Christopher Cogle, Ph.D.Professor, Department of Hematological Malignancies & Bone Marrow Transplantation, University of Florida, Gainesville, FL
Acute myeloid leukemia (AML) is highly refractory and there is pressing need for new therapeutics. Previously, we found that blood vessels are sanctuary sites for refractory AML. From this discovery, we screened a mixture-based combinatorial chemical library in a new bioassay of vasculature-associated AML cells. Positional scanning and deconvolution were used to identify the hit compound, 2470-51, which is a polyamide sulfonamide. Three distinct proteomics methods were used to discover the compound binding target, heterogeneous ribonucleoprotein C (hnRNPC). Downregulation of HNRNPC in AML cells results in decreased proliferation, viability, and failure to establish leukemia in immunodeficient mice. Patients with lower HNRNPC expression in their AML cells achieved improved survival outcomes. Protein thermal shift assays and minigene assays are now being used to identify highly potent hnRNPC inhibitors.
SESSION 3
PHENAZINE ANTIBIOTIC INSPIRED DISCOVERY OF BACTERIAL BIOFILM-ERADICATING AGENTS
Robert Huigens, Ph.D.Assistant Professor, Department of Medicinal Chemistry, University of Florida, Gainesville, FL
Bacterial biofilms are surface-attached communities of slow-growing and non-replicating persister cells that demonstrate high levels of antibiotic tolerance. Biofilms occur in nearly 80% of infections and present unique challenges to our current arsenal of antibiotic therapies, which were initially discovered for their abilities to target rapidly-dividing, free-floating planktonic bacteria. Bacterial biofilms are credited as the underlying cause of chronic and recurring infections. Innovative approaches are required to identify new small molecules that operate through bacterial growth-independent mechanisms to effectively eradicate biofilms. One source of inspiration comes from within the lungs of young Cystic Fibrosis (CF) patients, who often endure persistent Staphylococcus aureus infections.
As these CF patients age, Pseudomonas aeruginosa co-infects the lungs and utilize phenazine antibiotics to eradicate the established S. aureus infection. Our group is interested in this microbial competition strategy and we are currently
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investigating the potential of phenazine antibiotic-inspired compounds to eradicate persistent biofilms. We have established an interdisciplinary research program involving synthetic medicinal chemistry, microbiology and molecular biology aimed to discover new biofilm-eradicating agents. From these efforts, we have identified a series of halogenated phenazines (HP) that potently eradicate bacterial biofilms and future work aims to translate these preliminary findings into groundbreaking clinical advances for the treatment of persistent biofilm infections.
TB AND NOT TB: DISCOVERING NEW DRUGS FOR BAD BUGS
Kyle Rohde, Ph.D.Associate Professor, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL
Pathogenic mycobacteria include the leading infectious cause of mortality worldwide, M. tuberculosis (Mtb), as well as M. abscessus (Mab), an emerging non-tuberculous mycobacteria (NTM) that afflicts patients with cystic fibrosis and other underlying pulmonary conditions. The treatment of even drug susceptible Mtb and Mab strains is a daunting task, requiring multidrug regimens for 6 months to >1 year. Difficulties treating these infections stem not only from the emergence of multidrug resistant strains immune to front-line therapeutics but also from the presence of phenotypically drug tolerant populations dormant bacilli referred to as persisters. New, potent antibiotics
that inhibit novel targets are urgently needed that can effectively eradicate dormant and drug-resistant mycobacteria. My lab has developed a BSL3 drug screening facility at UCF where we employ luminescent reporter strains to identify compounds active against Mtb and Mab.
A novel aspect of our drug discovery strategy is a multi-stress Mtb dormancy model that mimics the in vivo environment to enrich for compounds with bactericidal activity towards nonreplicating persistors. Through ongoing collaborations with synthetic and medicinal chemists, we exploit our assay pipeline to discover novel antimycobacterial scaffolds and chemical probes. This talk will highlight the discoveries and lessons learned from exploitation of marine and fungal natural products as sources of new antibiotics targeting TB and NTM.
THE SEARCH FOR BETTER TUBERCULOSIS TREATMENTS
Charles Peloquin, Ph.D.Professor, Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL
Despite the availability of tuberculosis (TB) antimicrobials since the 1940s, TB remains the #1 infectious killer on the planet. TB is deeply associated with poverty, and it is spread by coughing. It can remain “latent” for years within an individual, only later presenting as active disease. Current treatments are long (over 6 months) and are associated with adherence issues, adverse effects, and drug-drug interactions. Renewed
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efforts on eliminating latent TB and shortening treatment of active disease, including drug resistant TB, are underway. New chemical entities and treatment strategies will be discussed.
SESSION 4
CHARACTERIZATION OF ADME PROPERTIES OF MITRAGYNINE, THE MAJOR ALKALOID OF MITRAGYNA SPECIOSA (KRATOM)
Abhisheak Sharma, Ph.D.Research Assistant Professor, Department of Pharmaceutics, University of Florida, Gainesville, FL
Kratom (Mitragyna speciosa) is a psychoactive plant native to Southeast Asia. It is self-prescribed for the treatment of pain and opioid withdrawal in the United States. Mitragynine, a major kratom alkaloid, is believed to be responsible for kratom’s therapeutic effects. A minor kratom alkaloid, 7-hydroxymitragynine, is a 46-fold more potent analgesic than mitragynine but it showed addiction potential in animal models. An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for the simultaneous quantification of mitragynine and 7-hydroxymitragynine in commercial kratom products. Higher levels of 7-hydroxymitragynine were observed in commercial kratom products than natural kratom. It could be due to the possible adulteration through artificial elevation of 7-hydroxymitragynine in commercial products. Further, a UPLC-MS/MS method was developed and validated for the
quantification of ten key alkaloids, namely: corynantheidine, corynoxine, corynoxine B, 7-hydroxymitragynine, isocorynantheidine, mitragynine, mitraphylline, paynantheine, speciociliatine, and speciogynine. The method would be useful for the quantification of key alkaloids in kratom products. In order to understand the ADME properties of mitragynine and its metabolic conversion to 7-hydroxymitragynine, a series of in vitro and in vivo experiments were performed. Results indicated that oral administration of mitragynine resulted in higher plasma exposure of 7-hydroxymitragynine than intravenous administration, suggesting a prominent role of intestinal metabolism, supported by the metabolism of mitragynine to 7-hydroxymitragynine in intestinal microsomes. As 7-hydroxymitragynine is a potent µ agonist, its systemic exposure due to the in vivo metabolism of mitragynine may potentially contribute to the overall pharmacological activity of mitragynine. Mechanistic studies are being conducted to evaluate the contribution of 7-hydroxymitragynine in the pharmacological activity of mitragynine.
KRATOM ALKALOIDS: IN VITRO AND IN VIVO PHARMACOLOGICAL MECHANISMS
Lance McMahon, Ph.D.Professor, Department of Pharmacodynamics, University of Florida, Gainesville, FL
The leaves of Mitragyna speciosa (kratom), a tree indigenous to Southeast Asia, are ground and ingested in boiled teas and
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capsules to achieve stimulant-like effects and/or to self-treat pain and opioid dependence. Kratom contains numerous alkaloids that yield a complex pharmacology. This talk provides an overview of the individual alkaloids contained in kratom. Pharmacological mechanisms to be considered include in vitro binding profiles at CNS targets and behavioral effects in pre-clinical assays predictive of abuse.
NOP-RELATED AGONISTS AS A TREATMENT OPTION FOR PAIN AND OPIOID ABUSE IN NON-HUMAN PRIMATES
Holden Ko, Ph.D.Professor, Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC
This presentation will provide an overview of behavioral neuropharmacology of nociceptin/orphanin FQ peptide (NOP) receptor-related agonists in non-human primates with three objectives. 1) To investigate the therapeutic potential of NOP agonists as spinal analgesics without mu opioid peptide (MOP) agonist-associated itch side effect. 2) To establish the functional profile of systemic NOP agonists as safe, non-addictive analgesics. 3) To develop a framework of bifunctional NOP/MOP agonists with a dual therapeutic action for treatment of pain and opioid use disorder. This presentation will allow attendees to learn how pharmacological studies in non-human primates facilitate translational studies of NOP-related agonists for therapeutic applications for treating pain and opioid abuse.
THE DIVERSITY OF CYCLIC TETRAPEPTIDES: STRUCTURE-ACTIVITY RELATIONSHIP LESSONS LEARNED FOR SAFER ANALGESICS
Jane Aldrich, Ph.D.Professor, Department of Medicinal Chemistry, University of Florida, Gainesville, FL
The macrocyclic tetrapeptides CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) and its D-Trp isomer both bind to kappa opioid receptors (KOR) and exhibit KOR antagonist activity. The change in the tryptophan stereochemistry, however, changes the in vivo opioid activity profile; while the D-Trp isomer exhibits KOR antagonism with minimal agonist activity, CJ-15,208 containing L-Trp exhibits mixed agonist/KOR antagonist activity in a mouse antinociceptive assay (Ross et al., 2012). Therefore we explored the effects of changing the stereochemistry of the phenylalanine residues on opioid activity. The peptides were synthesized by a combination of solid phase synthesis of the linear precursors followed by cyclization of the peptides in dilute solutions using optimized reaction conditions. All of the new stereoisomers examined exhibited antinociceptive activity in vivo in the mouse 55 oC warm-water tail-withdrawal assay, with multiple opioid receptors contributing to the antinociceptive activity. However, unlike the lead peptides most of the stereoisomers did not exhibit KOR antagonism. Several of the stereoisomers were also active after oral administration and some exhibited promising results in tests for liabilities associated with
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standard narcotic analgesics (sedation, tolerance). Thus these peptides represent new lead compounds for the potential development of novel analgesics. Research supported by NIDA grants R01 DA18832 and R01 DA023924.
REFINEMENT OF CYCLIC TETRAPEPTIDE MULTIFUNCTIONAL OPIOID AGONIST/ANTAGONISTS AS SAFER ANALGESICS AND TREATMENTS FOR OPIOID ADDICTION
Jay McLaughlin, Ph.D.Associate Professor, Department of Pharmacodynamics, University of Florida, Gainesville, FL
Kappa opioid receptor (KOR) selective agonists reverse acute intoxication and rewarding effects of abused substances, but the associated dysphoria precludes their clinical use. It has been long hypothesized that multifunctional drugs possessing both kappa- and mu-opioid receptor (MOR) agonist effects might minimize dysphoria while still suppressing drug-induced reward, but this idea has never been tested methodically with structurally similar compounds. Here, we examined a trio of macrocyclic tetrapeptides possessing multifunctional KOR antagonism and mixed opioid agonism, but each with differing ratios of MOR and KOR activity to evaluate the balance of mixed MOR/KOR agonism that would minimize liabilities while preserving the therapeutic ability to suppress the rewarding effects of morphine. Tetrapeptides CJ-15,208 (Ross et al., 2012) and [Ala1,D-Trp4]CJ-15,208 (Aldrich et al., 2014)
produced equipotent antinociception in the 55oC warm-water tail-withdrawal test using wild-type C57BL/6J mice, with ED50 (and 95%CI) values of 1.74(0.62-4.82) and 3.03(2.16-4.59) nmol, icv, respectively, whereas Compound 1 was 15-fold more potent (0.11(0.05-0.21) nmol, i.c.v.). Using MOR knockout (MOR KO) and KOR knockout (KOR KO) mice, CJ-15,208 showed an equal mix of MOR and KOR agonism, whereas [Ala1,D-Trp4]CJ-15,208 antinociception was predominantly KOR mediated and Compound 1 was predominantly MOR mediated. Sedation and respiratory depression were evaluated in the rotorod assay and CLAM system, but no compound produced sedation at doses up to 100 nmol icv. CJ-15,208 produced initial conditioned place aversion (CPA) at a 3 nmol icv dose, but at [higher doses demonstrated MOR-mediated conditioned place preference (CPP). In contrast, [Ala1,D-Trp4]CJ-15,208 (3 nmol icv) was without effect in the conditioned place preference assay, but demonstrated CPA at higher doses. Both of these effects were absent in KOR KO mice. Notably, Compound 1 demonstrated only modest CPP only at higher doses. Of interest, only [Ala1,D-Trp4]CJ-15,208 prevented acute morphine-CPP, but all three compounds blocked stress-induced reinstatement of extinguished morphine-CPP. In conclusion, the addition of KOR to MOR agonism alleviates some liabilities attributed to receptor-selective agonists, although a greater ratio of MOR/KOR agonist activity proved detrimental at higher doses, suggesting an upper limit to the desired amount of MOR agonism.
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GRADUATE STUDENTS & RESEARCHINTERNS/TRAINEES
1. ONE-POT BIOCOMBINATORIAL SYNTHESIS OFHERBICIDAL THAXTOMINS AND SUBSTITUTEDAROMATIC 2,5-DIKETOPIPERAZINES
Presenter: Guangde JiangDepartment of Medicinal Chemistry, College of Pharmacy, University of Florida
2. DISPATCHING THE UBIQUITOUS RADICAL SAMENZYMES BYPRODUCT 5-DEOXYRIBOSE
Presenter: Qiang LiDepartment of Chemistry, College of Liberal Arts and Sciences, University of Florida
3. DECODING THE SELF-RESISTANCE MECHANISMOF BACTERIA LINKED WITH COLORECTAL CANCER.
Presenter: Prabhanshu TripathiDepartment of Chemical Biology, College of Liberal Arts and Sciences, University of Florida
4. ELUCIDATING THE BIOSYNTHESIS OFMICROVIRIDINS: A STRUCTURAL APPROACH
Presenter: Krishna Patel and Gengnan LiDepartment of Chemistry, College of Liberal Arts and Sciences, University of Florida
5. BIOCHEMICAL AND STRUCTURALCHARACTERIZATION OF CYANOBACTERIALDIHYDROXYACID DEHYDRATASE
Presenter: Brian MacTavishDepartment of Chemistry, College of Liberal Arts and Sciences, University of Florida
6. A NOVEL FAMILY OF FUNGAL GLYCAN BINDINGPROTEINS POSSESSES DIVERSE GLYCAN SPECIFICITY
Presenter: Peilan ZhangDepartment of Medicinal Chemistry, College of Pharmacy, University of Florida
7. GENOMIC AND TARGETED APPROACHESTOWARDS THE MECHANISM OF ACTION OFTHE ANTIFUNGAL CYTOTOXIN AMANTELIDE AISOLATED FROM A MARINE CYANOBACTERIUM
Presenter: Lobna ElsadekDepartment of Medicinal Chemistry, College of Pharmacy, University of Florida
8. BIOSYNTHESIS OF SPHINGOLIPID ANALOGUESBY ENGINEERED ACYL-COA UTILIZING SERINEPALMITOYLTRANSFERASE
Presenter: Hyunjun ChoeDepartment of Chemistry, College of Liberal Arts and Sciences, University of Florida
» POSTER PRESENTATIONS
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9. INVESTIGATION OF COMPOUNDS PRODUCED BY PROBIOTIC BACTERIA ISOLATED FROM HEALTHY CORAL ON FLORIDA REEFS
Presenter: Sharon ThompsonSmithsonian Marine Station at Fort Pierce, Smithsonian Institution, Florida
10. CHEMISTRY AND BIOLOGY OF ANAEPHENES A-C AND THE ANAENOIC ACIDS, NEW NATURAL PRODUCTS DERIVED FROM MARINE FILAMENTOUS CYANOBACTERIA
Presenter: David BrumleyDepartment of Medicinal Chemistry, College of Pharmacy, University of Florida
11. DISCOVERY OF SURVIVIN-TARGETING MARINE NATURAL PRODUCTS
Presenter: Kirstie TandbergDepartment of Integrative Biology, Charles E. Schmidt College of Science Harbor Branch Oceanographic Institute, Florida Atlantic University
12. ISOLATION OF SECONDARY METABOLITES FROM ANTARCTIC SPONGE ARTEMISINA PLUMOSA FOR POTENTIAL DNA TOPOISOMERASE I INHIBITION
Presenter: Joshua WelschDepartment of Chemistry, College of Arts and Sciences, University of South Florida
13. DISCOVERY OF PHEROMONES AND NATURAL PRODUCTS BY COMPARATIVE METABOLOMICS APPROACH IN C. ELEGANS
Presenter: Subhradeep BharDepartment of Chemistry, College of Liberal Arts and Sciences, University of Florida
14. BIOASSAY-GUIDED ISOLATION OF MANGROVE FUNGAL SECONDARY METABOLITES AGAINST TUBERCULOSIS
Presenter: Bingjie YangDepartment of Chemistry, College of Liberal Arts and Sciences, University of Florida
15. A NEW CLASS OF ORGANOSULFUR COMPOUNDS ACTIVE AGAINST HER2+ AND EGFR+ BREAST CANCER CELLS
Presenter: Amanda Ghilardi and Elham YaaghubiDepartment of Chemistry, College of Liberal Arts and Sciences, University of Florida
16. METABOLOMICS OF INTESTINAL BACTERIA FOR NOVEL KIDNEY STONE THERAPEUTICS
Presenter: Casey ChamberlainDepartment of Pathology, College of Medicine, University of Florida
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17. OPTIMIZATION OF TARGETED FUNGAL SECONDARY METABOLITE PRODUCTION USING LC-MS METABOLOMICS
Presenter: Anne-Claire LimonDepartment of Chemistry, College Arts and Sciences, University of South Florida
18. PRODRUG MODIFICATION OF DOXORUBICIN FOR HIGH DRUG LOADING INTO NANOPARTICLES CAPABLE OF MPI IMAGING
Presenter: Eric FullerDepartment of Biomedical Engineering, College of Engineering, University of Florida
19. MURINE ORGANOID-BASED DRUG SCREEN IDENTIFIES NOVEL INHIBITORS OF PANCREATIC ACINAR DUCTAL METAPLASIA
Presenter: Lais WrightDepartment of Pharmaceutics, College of Pharmacy, University of Florida
20. SYNTHESIS OF SMALL MOLECULES FOR PROTEIN CONTROL
Presenter: Elena BrayDepartment of Chemistry, College of Arts and Science, University of South Florida
21. DEVELOPMENT OF A SELECTIVE PHOSPHATASE INHIBITOR
Presenter: Jamie NunziataDepartment of Chemistry, College of Arts and Sciences, University of South Florida
22. IMPROVING THE PREDICTION OF PROTEIN-LIGAND BINDING AFFINITY USING DEEP LEARNING MODELS
Presenter: Mohammad RezaeiDepartment of Medicinal Chemistry, College of Pharmacy, University of Florida
23. SYNTHESIS AND ANTIBACTERIAL TESTING OF ALKYL THIOSULFONATES
Presenter: Lindsay BlumeDepartment of Chemistry, College of Liberal Arts and Sciences, University of Florida
24. BIOCHEMICAL AND BIOLOGICAL STUDIES OF HUMAN PRMT5 AND ITS STRUCTURE-BASED DESIGNER SMALL MOLECULE INHIBITORS FOR POTENTIAL CANCER THERAPEUTICS
Presenter: Wei ZhouDepartment of Biochemistry, College of Medicine, University of Florida
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25. PRELIMINARY INVESTIGATION OF EXOCYCLIC AMINE MOIETIES IN BENZOTHIAZOLONE-BASED Σ1 RECEPTOR LIGANDS
Presenter: Hebaalla AghaDepartment of Medicinal Chemistry, College of Pharmacy, University of Florida
26. STRUCTURAL STUDY OF CARBONIC ANHYDRASE IX; NOVEL SMALL MOLECULE INHIBITORS FOR TRIPLE NEGATIVE BREAST CANCER
Presenter: Jacob AndringDepartment of Biochemistry, College of Medicine, University of Florida
27. TOWARDS THE DEVELOPMENT OF CARBOHYDRATE CANCER VACCINES
Presenter: Brittany SmithDepartment of Chemistry, College Liberal Arts & Sciences, University of Florida
28. RESPONSIVE FLUOROPHORE AGGREGATION PROVIDES CONTRAST FOR LIFETIME IMAGING IN CELLS
Presenter: Kelton SchleyerDepartment of Medicinal Chemistry, College Pharmacy, University of Florida
29. HALOGENATED PHENAZINES AS POTENT BIOFILM-ERADICATING AGENTS SYNTHESIZED THROUGH AN OPTIMIZED WOHL-AUE ROUTE
Presenter: Hongfen YangDepartment of Medicinal Chemistry, College of Pharmacy, University of Florida
30. KRATOM TEA AS A THERAPEUTIC FOR OPIOID ABUSE
Presenter: Lisa WilsonDepartment of Pharmacodynamics, College of Pharmacy, University of Florida
31. HIV-TAT PROTEIN MODULATES COGNITIVE PERFORMANCE THROUGH INDUCTION OF HYPERGLUTAMATERGIC SIGNALING IN BRAIN
Presenter: Thomas CirinoDepartment of Pharmacodynamics, College of Pharmacy, University of Florida
32. ANALOGS OF THE SELECTIVE SIGMA-1 RECEPTOR ANTAGONIST CM-304 PRODUCE ENDURING ANTINOCICEPTION WITHOUT SEDATION
Presenter: Amy AlleyneDepartment of Pharmacodynamics, College of Pharmacy, University of Florida
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33. SYNTHESIS OF RHODACYANINE DERIVATIVES AS HSP70 INHIBITORS FOR IMPROVED TAU DEGRADATION IN TAUOPATHIES
Presenter: Andrea LemusDepartment of Chemistry, College of Arts and Sciences, University of South Florida
34. ASSESSMENTS OF THE INVOLVEMENT OF ALPHA2-ADRENERGIC RECEPTORS IN THE DISCRIMINATIVE STIMULUS EFFECTS OF TYPICAL AND ATYPICAL OPIOIDS IN RATS
Presenter: Morgan ReevesDepartment of Pharmacodynamics, College of Pharmacy, University of Florida
35. COMPUTATIONALLY-DESIGNED MIXED MU-KAPPA OPIOID AGONIST, UM1207, DISPLAYS POTENT ANALGESIA WITH REDUCED ADDICTION AND RESPIRATORY LIABILITY
Presenter: Chloe SimonsDepartment of Pharmacodynamics, College of Pharmacy , University of Florida
36. THE SIGMA1 RECEPTOR ANTAGONIST CM304 ENHANCES THE ANTINOCICEPTIVE EFFECTS OF CANNABINOID CB1 AGONISTS, BUT NOT MU-OPIOID RECEPTOR AGONISTS, IN MICE
Presenter: Avi PatelDepartment of Pharmacodynamics, College of Pharmacy , University of Florida
37. STRUCTURE-BASED DRUG DESIGN TOWARDS SMALL MOLECULE INTERLEUKIN-6 INHIBITORS
Presenter: Daniel SchultzDepartment of Medicinal Chemistry, College of Pharmacy, University of Florida
38. SAR OF KAVALACTONES IN BLOCKING LUNG TUMORIGENESIS INDUCED BY TOBACCO-SPECIFIC CARCINOGEN NNK
Presenter: Qi HuDepartment of Medicinal Chemistry, College of Pharmacy, University of Florida
39. OPTIMIZING THE ANTI-PROLIFERATIVE ACTIVITY OF CJ-15,208 IN PROSTATE CANCER
Presenter: Robyn PescatoreDepartment of Medicinal Chemistry, College of Pharmacy, University of Florida
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POSTDOCTORAL FELLOWS
40. EFFECTS AND MECHANISMS OF NNAL, A MAJOR IN VIVO METABOLITE OF NNK, ON LUNG CANCER CELL LINE GROWTH, MIGRATION, AND DRUG RESISTANCE
Presenter: Tengfei BianDepartment of Medicinal Chemistry, College of Pharmacy, University of Florida
41. NOVEL CARBAPENEM DERIVATIVES WITH ENHANCED ANTIMICROBIAL ACTIVITY AGAINST M. TUBERCULOSIS AND M. ABSCESSUS
Presenter: Rashmi GuptaBurnett School of Biomedical Science, College of Medicine, University of Central Florida
42. SYNTHESIS AND CHARACTERIZATION OF XL34754 AS A NOVEL BCL-XL DEGRADER
Presenter: Xingui LiuDepartment of Pharmacodynamics, College of Pharmacy, University of Florida
43. REACTIVE GLIOSIS CONTRIBUTES TO NRF2-DEPENDENT NEUROPROTECTION BY PRETREATMENT WITH DIMETHYL FUMARATE OR KOREAN RED GINSENG AGAINST HYPOXIC-ISCHEMIA: FOCUS ON HIPPOCAMPAL INJURY
Presenter: Lei LiuDepartment of Anesthesiology, College of Medicine, University of Florida
44. SELF-IMMOBILIZING NIR PROBE FOR IMAGING OF CELLULAR SENESCENCE IN VIVO
Presenter: Jun LiuDepartment of Medicinal Chemistry, College of Pharmacy, University of Florida
45. A NOVEL COMPOUND INHIBITING PSEUDOMONAS AERUGINOSA AMPG GREATLY REDUCES THE TRANSPORT OF SIGNALING MOLECULES FOR INDUCIBLE AMPC Β-LACTAMASE EXPRESSION AND RESISTANCE TO Β-LACTAM ANTIBIOTICS
Presenter: Young KimDepartment of Molecular Genetics and Microbiology, College of Medicine, University of Florida
46. DISCOVERY OF BCL-XL DEGRADERS AS POTENT AND SAFE ANTICANCER AGENTS
Presenter: Xuan ZhangDepartment of Medicinal Chemistry, College of Pharmacy, University of Florida
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47. SYNTHESIS OF TETRASACCHARIDE SUBSTRATES OF HEPARANASE
Presenter: Rina SaksenaDepartment of Medicinal Chemistry, College of Pharmacy, University of Florida
48. TRYPTOLINE INDUCED C-N BOND CLEAVAGE OF INDOLE ALKALOIDS: A PLATFORM TO GENERATE NOVEL SMALL MOLECULES FOR DRUG DISCOVERY
Presenter: Alejandra Chavez-RiverosDepartment of Medicinal Chemistry, College of Pharmacy, University of Florida
49. MAPPING THE ACTIVITIES OF HEPARANASE WITH SYNTHETIC DISACCHARIDES
Presenter: Meijun XiongDepartment of Medicinal Chemistry, College of Pharmacy, University of Florida
RESEARCH FACULTY/STAFF
50. PROSPECTIVE STUDY FOR ANTITUMORAL AGENTS FROM THE SEA HARE APLYSIA DACTYLOMELA
Presenter: Rodrigo KitagawaDepartment of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development, College of Pharmacy, University of Florida
51. SCREENING OF INDUCERS OF THE NRF2/ARE PATHWAY FROM THE BROWN ALGA PADINA GYMNOSPORA
Presenter: Rita GoncalvesDepartment of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development College of Pharmacy, University of Florida
52. APPLICATION OF A COMBINATORIAL NATURAL PRODUCT THERAPY FOR THE TREATMENT OF HIGH-GRADE GLIOMAS.
Presenter: Hassan AzariDepartment of Neurosurgery, College of Medicine, University of Florida
53. CARRIEBOLIDE A AND CARRIEBOLIDE B FROM TWO MARINE CYANOBACTERIA FROM CARRIE BOW CAY, BELIZE
Presenter: Sarath GunasekeraSmithsonian Marine Station at Fort Pierce, Smithsonian Institution
54. IN VITRO EVALUATION OF CIMETIDINE RENO-PROTECTIVE EFFECTS ON CISPLATIN-INDUCED KIDNEY INJURY (CIKI)
Presenter: Bihorel SihemDepartment of Pharmaceutics, College of Pharmacy, University of Florida
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GRADUATE STUDENTS
1. DITERPENOIDS DERIVED FROM THE ANTARCTIC SPONGE DENDRILLA MEMBRANOSA DISPLAY POTENT ACTIVITY IN INFECTIOUS DISEASE SCREENING.
Andrew J. Shilling,1 Alexandre M. Bory,1 Jessie Adams,2 Ala Azhari,3 Christopher Rice,4 Alison Roth,3 Christopher G. Witowski,1 J. Alan Maschek,1 Lindsey N. Shaw,2 John H. Adams,3 Dennis E. Kyle,4 Charles D. Amsler,5 James B. McClintock,5 Bill J. Baker*1 1Department of Chemistry, 2Department of Cell Biology, Microbiology, and Molecular Biology, 3Department of Global Health, College of Public Health, University of South Florida, Tampa, FL. 4Department of Infectious Diseases, Department of Cellular Biology, University of Georgia, Athens, GA 5Department of Biology, University of Alabama at Birmingham, Birmingham, AL
2. MIXED OPIOID RECEPTOR AGONISM AND ANTAGONISM DEMONSTRATED BY A NOVEL CYCLIC TETRAPEPTIDE PREVENTS DRUG- AND STRESS-INDUCED REINSTATEMENT OF DRUG-SEEKING BEHAVIOR.
Ariana C. Brice-Tutt,1 Lisa L.Wilson,1 Shainnel O. Eans,1 Heather M. Stacy,1 Chloe A. Simons,1 Grant Simpson,2 Jeremy S. Coleman,2 Michael J. Ferracane,2 Jane V. Aldrich,2 Jay P. McLaughlin*11Department of Pharmacodynamics and 2Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL
3. PREVENTING MORPHINE SEEKING BEHAVIOR THROUGH THE RE-ENGINEERING OF VINCAMINE’S BIOLOGICAL ACTIVITY.Verrill M. Norwood IV,1,2 Robert W. Huigens III*1,21Department of Medicinal Chemistry, 2Center for Natural Products, Drug Discovery and Development (CNPD3), College of Pharmacy, University of Florida, Gainesville, FL
4. SIMPLE, TUNABLE SYNTHETIC ROUTES TO CANNABINOID NATURAL PRODUCT ANALOGUESPrimali V. Navaratne,1 Ion Ghiviriga,1 Alexander J. Grenning*11Department of Chemistry, University of Florida, Gainesville, FL
5. RECONSTITUTION OF THE BIOSYNTHESIS OF MULTIPLE MICROVIRIDIN CORE PEPTIDES REVEALS SYNERGY BETWEEN PROCESSING ENZYMES.Yi Zhang,1,2 Gengnan Li,3 Krishna Patel,3 Michael H Patterson,4 Steven D Bruner,2,3 Yousong Ding*1,21Department of Medicinal Chemistry, 2Center for Natural Products, Drug Discovery and Development, College of Pharmacy, 3Department of Chemistry, 4Department of Chemical Engineering, Herbert Wertheim College of Engineering, University of Florida, Gainesville, FL
6. DISCOVERY, TOTAL SYNTHESIS AND SAR OF A NOVEL QUORUM SENSING SIGNALING MOLECULE FROM A MARINE CYANOBACTERIUM.Xiao Liang,1,2 Susan Matthew,1 Qi-Yin Chen,1,2 Jason C. Kwan,1 Valerie J. Paul,3 Hendrik Luesch*1,21Department of Medicinal Chemistry, 2Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, FL. 3Smithsonian Marine Station, Fort Pierce, FL
» ORAL PRESENTATIONS
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7. CELL-SELECTIVE METABOLIC ENGINEERING FOR LABELING GPI ANCHORED PROTEINS IN CANCER CELLS
Mohit Jaiswal,1 Sanyong Zhu,1 Zhongwu Guo*11Department of Chemistry, University of Florida, Gainesville, FL
POSTDOCTORAL FELLOWS
1. WATER SOLUBLE CHEMICAL CUES FOR CORAL LARVAE: STRATEGIES FOR ISOLATING WATER SOLUBLE DRUG LEADS
Skylar Carlson,1 Jennifer Sneed,1 Sarath Gunasekera,1 Danielle L. Dixson,2 Valerie J. Paul*11Smithsonian Marine Station, Fort Pierce, FL, 2College of Earth, Ocean and Environment, University of Delaware, Newark, DE
2. DISCOVERY OF FUNGAL NATURAL PRODUCTS TARGETING DORMANT M. TUBERCULOSIS AND M. ABSCESSUS
Marisa A. Fuse,1 Shengxin Cai,2 Robert H. Cichewicz,2 Kyle H. Rohde*1 1Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 2Natural Products Discovery Group, University of Oklahoma, Norman, OK
3. SYNTHESIS AND PRELIMINARY PHARMACOLOGICAL EVALUATION OF NEW Σ RECEPTOR LIGANDS WITH ANTI-NEUROPATHIC PAIN EFFECTS IN MICE
Sebastiano Intagliata1, Lisa Wilson2, Amy Alleyne2, Heather M. Stacy2, Shyam H. Kamble3, Abhisheak Sharma,3 Jasmine Cano,4 Talia Kawesa,4 Lawrence Toll,4 Bonnie A. Avery, 3Jay P. McLaughlin,2 Christopher R. McCurdy*11Department of Medicinal Chemistry, 2Department of Pharmacodynamics, 3Department of Pharmaceutics, University of Florida, Gainesville, FL, 4Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL USA
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UF DRUG DISCOVERY SYMPOSIUM JUDGES & SESSION CHAIRS
THANK YOU TO OUR JUDGES AND THE SESSION CHAIRS
ORAL PRESENTATION JUDGESJohn MacMillanPaul KennyChris XingBen ShenHolden KoChenglong Li
POSTER PRESENTATION JUDGESAmy LaneJeffrey RudolfYousong DingKyle RohdePredag CudicGuangrong ZhengBrian LawBrandon WarrenRob HuigensFrancisco Leon Oyola
UF DRUG DISCOVERY SYMPOSIUM SPONSORS
PLATINUM
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UF DRUG DISCOVERY SYMPOSIUM SPONSORS
PLATINUM
GOLD
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