SOLUTION STRUCTURE OF A CYCLIC RGD PEPTIDE THAT INHIBITS PLATELET-AGGREGATION

Peptides containing the Arg-Gly-Asp (RGD) sequence can inhibit platele t aggregation. Incorporation of this sequence into a cyclic peptide re sults in specific binding to a particular integrin. Studies of cyclic RGD peptides show that residues surrounding the RGD sequence have impo rtant effects on the selectivity of the peptide to bind with glycoprot ein IIb/IIIa (GPIIb/IIIa). In this paper, we elucidate the conformatio n of Gly3-His4-Arg5-Gly6-Asp7-Leu8-Arg9-Cys10-Ala11-NH2 (1) by NMR and molecular dynamics simulations. This peptide inhibits platelet aggreg ation in a manner similar to that reported for -Gly3-His4-Arg5-Gly6-As p7-Leu8-Arg9-Cys10-Ala11-OH (6) (Cheng, S. et al. J. Med. Chem. 1994, 37, 1-8), which is shown to be selective for the GPIlb/IIIa receptor. The cyclic peptide 1 exhibited a major and a minor conformer in soluti on. In the major conformer, the His4-Arg5-Gly6-Asp7 segment encompasse s a 4-->1 hydrogen bond with a distorted type II beta-turn, and the mi nor conformer has turn-extended-turn. A comparison between the major c onformation of this peptide and those of other cyclic RGD peptides sug gests the importance of a hydrophobic residue adjacent to the RGD sequ ence.