Solution Structure of a Cyclic RGD Peptide That Inhibits Platelet Aggregation

Abstract

Peptides containing the Arg-Gly-Asp (RGD) sequence can inhibit platelet aggregation. Incorporation of this sequence into a cyclic peptide results in specific binding to a particular integrin. Studies of cyclic RGD peptides show that residues surrounding the RGD sequence have important effects on the selectivity of the peptide to bind with glycoprotein Ilb/IIIa (GPIIb/lIIa). In this paper, we elucidate the conformation of cyclo(2,10)Ac-Glyl-Pen2- Gly3-His4-Arg5-Gly6-Asp7-Leu8-Arg9-Cys 10-Ala 11 -NH₂ (1) by NMR and molecular dynamics simulations. This peptide inhibits platelet aggregation in a manner similar to that reported for cyclo(2,10)Glyl-Pen2-Gly3-His4-Arg5-Gly6-Asp7-Leu8-Arg9-Cysl0-Alal 1- OH (6) (Cheng, S. et al. J. Med. Chem. 1994, 37, 1–8), which is shown to be selective for the GPIIb/IIIa receptor. The cyclic peptide 1 exhibited a major and a minor conformer in solution. In the major conformer, the His4-Arg5-Gly6-Asp7 segment encompasses a 4—>1 hydrogen bond with a distorted type II β-turn, and the minor conformer has turn-extended- turn. A comparison between the major conformation of this peptide and those of other cyclic RGD peptides suggests the importance of a hydrophobic residue adjacent to the RGD sequence.