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A three‐residue cyclic scaffold of non‐RGD containing peptide analogues as platelet aggregation inhibitors: Design, synthesis, and structure–function relationships
Author(s) -
Stavrakoudis Athanassios,
Bizos George,
Eleftheriadis Damianos,
Kouki Aggeliki,
PanouPomonis Eugenia,
SakarellosDaitsiotis Maria,
Sakarellos Constantinos,
Tsoukatos Demokritos,
Tsikaris Vassilios
Publication year - 2000
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/1097-0282(2000)56:1<20::aid-bip1039>3.0.co;2-k
Subject(s) - chemistry , scaffold , cyclic peptide , platelet aggregation , residue (chemistry) , peptide , stereochemistry , function (biology) , platelet , combinatorial chemistry , biochemistry , microbiology and biotechnology , immunology , biology , medicine , biomedical engineering
Antagonists of fibrinogen at the GPIIb/IIIa receptor, which is the most abundant membrane protein on the platelet surface, are under active investigation as potential antithrombotics. The critical interaction between GPIIb/IIIa and fibrinogen can be inhibited by either linear or cyclic RGDS‐containing peptides, which have been proved as lead compounds in the design of platelet aggregation inhibitors. In this study we present the design and construction of a new class of cyclic (S,S) non‐RGD containing peptide sequences, using two Cys as a structural scaffold for the development of antiaggregatory agents. The (S,S)–CDC– sequence was incorporated as a conformational constraint, in molecules bearing at least one positive charge with the general formula (S,S)XCDCZ, where X = Ac–Arg, Pro–Arg, Pro–Ser–Lys, and Pro–Ser–Arg, and Z = –NH 2 and Arg–NH 2 . Investigation of the structure–function relationships was performed on the basis of (a) the local conformation induced by the (S,S)–CDC motif, (b) the distance of the positively (R–C ζ or K–N ζ ) and negatively (D–C γ ) charged centers, (c) the presence of a second positive or negative charge on the molecule, and (d) the orientation of the basic and acidic side chains defined by the pseudo dihedral angle (Pdo), which is formed by the R–C ζ , R–C α , D–C α , and D–C γ atoms in the case of (S,S)–RCDC and by the K–N ζ , K–C α , D–C α , and D–C γ atoms in the case of (S,S)–KCDC. © 2001 John Wiley & Sons, Inc. Biopolymers 56: 20–26, 2001