conformational analysis of -peptides
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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
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