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

Abstract

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

Effect of synthetic peptides corresponding to residues 313–332 of the αIIb subunit on platelet activation and fibrinogen binding to αIIbβ3

“…Thus, we assume that the YMES sequence may play an important role in modifying the RAD conformation in such a way that leads to the enhancement of the RAD‐mediated biological effects. However, we may not exclude the possibility that the decrease in the biological potency of the octapeptides II and III compared to octapetide I, may also be due to the prolongation of their C‐terminal portion, although we have shown previously that the presence of a second positive charge (R) at the C‐terminal part of RGD‐containing peptides significantly enhances their biological potency [30]. Further studies aiming to elucidate this assumption are currently in progress in our laboratory.…”

The relative orientation of the Arg and Asp side chains defined by a pseudodihedral angle as a key criterion for evaluating the structure–activity relationship of RGD peptides

“…In a previous work on RGD peptides some very potent inhibitors of the human platelet aggregation (IC 50 = 1-10 µM) were reported [55,56]. The IC 50 values are 10-20 times lower in inhibiting the fibrinogen binding to activated human platelets (unpublished data).…”

“…Incorporation of the RGD sequence in analogue 1 resulted in a two-fold increase of the antiaggregatory activity compared with Ac-RGD-NH 2 . Ac-SRGDVGRAibGK(Ac)AibG (1) 219 Ac-SRGDVGNleAibGK(Ac)AibG (2) 2000 Ac-SNleGDVGRAibGK(Ac)AibG (3) >2000 Ac-RAibGDAibGRAibGK(Ac)AibG (4) >2000 (S,S) Ac RCDCR-NH 2 4.3 a (S,S) PRCDCK-NH 2 10.6 a (S,S) Ac-RCDC-NH 2 105 a Ac-RGD-NH 2 ∼500 a a From reference [55].…”

Insights into the structure of the PmrD protein with molecular dynamics simulations

“…This interaction resembles the well-known RGD motif responsible for cell adhesion processes [27]. Side chain interactions between arginine and aspartic side chains have been studied with NMR and MD approaches [28][29][30][31] in model peptides. It has been proposed that carboxylic and guanidinium groups are directed in a synplanar orientation and that arrangement facilitates the binding process.…”