A three-residue cyclic scaffold of non-RGD containing peptide analogues asplatelet aggregation inhibitors: Design, synthesis, and structure-functionrelationships

Antagonists of fibrinogen at the GPIIb/IIIa receptor, which is the most abu ndant membrane protein on the platelet surface, are tinder active investiga tion as potential antithrombotics. The critical interaction between GPIIb/I IIa and fibrinogen can be inhibited by either linear or cyclic RGDS-contain ing peptides, which have been proved as lead compounds in the design of pla telet aggregation inhibitors. In this study we present the design and const ruction of it new class of cyclic (S,S) non-RGD containing peptide sequence s, using two Cys cis a structural scaffold for the development of antiaggre gatory agents. The (S,S)-CDC- sequence was incorporated as a conformational constraint, in molecules bearing at least one positive charge with the gen eral formula (S,S)XCDCZ, where X = Ac-Arg, Pro-Arg, Pro-Ser-Lys, and Pro-Se r-Arg, and Z = -NH2 and Arg-NH2. Investigation of the structure-function re lationships was performed on the basis of (a) the local conformation induce d by the (S,S)-CDC motif (b) the distance of the positively (R-C-zeta or K- N-zeta) and negatively (D-C-gamma) charged centers, (c) the presence of a s econd 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-zeta, R-C-alpha, D-C-alpha, and D-C-gamma atoms in the case of (S,S)-RCDC and by the K-A K-C-alpha, D-C-alpha, and D -C-gamma atoms in the case of (S,S)-KCDC (C) 2001 John Wiley & Sons, Inc.