Conformational Analysis of -Peptides

For a recent review, see: Chemistry & Biodiversity, 2004, 1, 1111.(available as PDF on Chem. 206 website)

Reviews: Biopolymers (Peptide Science) 2004, 76, 206-243 Tetrahedron 2004, 60, 7455-7506 Chemistry&Biodiversity 2004, 1, 1111-1239 J.Peptide Res. 2005, 65, 229-260 Biopolymers (Peptide Science) 2006, 84, 23

The -peptidic sheet

ACIE 1999, 38, 1595

(S)

(R)

R2H

N R3

H

R2

HR3

H

N

OO

HH

pleated-sheet element

CO2H

R2

HH2NCH2

CO2H

CH2

R3

HH2N

CO2H

R3

HH2N

H R2

"allowed" in sheet

(R)(R)

(S) (S)

nogem-disubstituted-amino acids!

HO

H

H

RN

H

N

H

HH3C

H

O

HCH3

H

apstrand ( sheet)

H

H

RN

H

OH

(+)sc

HN

H

HH3C

HH

CH3

O

turn ( helix)

Boc-3-HVal-3-HAla-3-HLeu-OMe in the CrystalHCA 1996, 79, 913

H

Comparison of Hairpin Structures of - and -PeptidesN C

N C

H

H

H

A1,3-effect

polar

polar+

+

-

-

unpolar

Helv. Chim. Acta 89, 361 - 403 (2006)

The (M)-314-helix

i

i+3

H

N R3

R2

H

O

H

R2

O

R3

H

N

helix elementH

H

CO2H

R2

CH2NH2H

CO2H

CH2

R3

HH2N

CO2H

R3

HH2N

R2 H

"allowed" in (M)-314-helix

2 3 2,3

(S)

(S)

(S)

(R)

(S)(S)

(S)

(S)

nogem-disubstituted-amino acids!

NMR-Solution Structure of a “Mixed” -Tridecapeptide

-Peptide: 314-(M)-Helix -Peptide: poor propensity for a stable secondary structure

……a demonstration of the large difference of folding preference between of - and -peptides R. I. Mathad, ETH Zuerich

-peptidic segment (6 residues) -peptidic segment (7 residues)

tetra-1h

nona-1h

octa-15 m

octa- 4h

(14C2)Ac-3hTyr-(R)Trp-3hLys-3hThr-OH (tetramer)

(14C2)Ac-(3hArg)8-NH2 (octamer)

H-3hAla-3hLys-3hPhe-3hAla-3hLys-(14C2)3hPhe--3hAla-3hLys-3hPheOH (nonamer)

ADME Investigationsp.o. bioavailable (25% after 15 min; 2mg/kg)totally cleared from body in 4 daysexcretion through feces and urine•15nM affinity to somatostatin hsst4 receptormetabolically stable

no p.o. bioavailability 50% cleared from body 7 days after i.v. (5mg/kg)excretion through feces and urine, not bile•inhibitor of SRB1 enzyme in CaCo-2 cellsmetabolically stable

no p.o. bioavailability totally cleared from body 1 day after p.o.<2 % clearance in 7 days after i.v. (1mg/kg)redistribution in body over time•cell-penetrating HeLa, keratinocyte cells metabolically stable

Biopharm. Drug Dispos. 2002, 23, 251 CBD 2004, 1, 1812

Chemistry & Biodiversity 2007, 4, 1413

Structure of Medium-Size Rings