A three-residue cyclic scaffold of non-RGD containing peptide analogues as platelet aggregation inhibitors: Design, synthesis, and structure-function relationships

• Published in: Biopolymers 2000, Vol.56 (1), p.20-26
• Main Authors: Stavrakoudis, Athanassios, Bizos, George, Eleftheriadis, Damianos, Kouki, Aggeliki, Panou-Pomonis, Eugenia, Sakarellos-Daitsiotis, Maria, Sakarellos, Constantinos, Tsoukatos, Demokritos, Tsikaris, Vassilios
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; cyclic non-RGD containing analogues; cyclization on solid support; cystine non-RGD analogues; disulfide bond formation; Drug Design; Electrochemistry; Humans; In Vitro Techniques; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - pharmacology; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; platelet aggregation inhibitors; Platelet Aggregation Inhibitors - chemical synthesis; Platelet Aggregation Inhibitors - chemistry; Platelet Aggregation Inhibitors - pharmacology; Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors; Protein Conformation; Structure-Activity Relationship; Thermodynamics
• ISSN: 0006-3525; 1097-0282
• DOI: 10.1002/1097-0282(2000)56:1<20::AID-BIP1039>3.0.CO;2-K

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 = –NH2 and Arg–NH2. 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–Cζ or K–Nζ) and negatively (D–Cγ) 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–Cζ, R–Cα, D–Cα, and D–Cγ atoms in the case of (S,S)–RCDC and by the K–Nζ, K–Cα, D–Cα, and D–Cγ atoms in the case of (S,S)–KCDC. © 2001 John Wiley & Sons, Inc. Biopolymers 56: 20–26, 2001