MULTIPLE SOLUTION CONFORMATIONS OF THE INTEGRIN-BINDING CYCLIC PENTAPEPTIDE CYCLO(-SER-D-LEU-ASP-VAL-PRO-) ANALYSIS OF THE (PHI,PSI)-SPACE AVAILABLE TO CYCLIC PENTAPEPTIDES

The aqueous solution structure of the cyclic pentapeptide cyclo(-Ser-D -Leu-Asp-Val-Pro-) has been determined by two-dimensional H-1-NMR spec troscopy, combined with a conformational search and distance-geometry calculations. As many as five conformers in slow exchange were observe d, and the rate of interconversion between components was measured fro m the build-up rates of exchange peaks. NMR data allowed the structure s of the two predominant conformers to be determined. The major compon ent (66%) contained a cis-proline as part of a type-VIa2 beta-turn enc ompassing residues Asp-Val-cis-Pro-Ser. The second component (16%) con tained only trans-amide bonds, and a type-VIII beta-turn formed by res idues Val-Pro-Ser-D-Leu. These structures are discussed in relation to the (phi,psi) space available to the cyclic pentapeptide, determined by a conformational search, and in relation to previously published cy clic-pentapeptide structures. The molecule exhibits activity in a scin tillation-proximity assay for the inhibition of the interaction betwee n the integrin very-late antigen-4 (VLA-4; alpha(4) beta(1)) and vascu lar-cell-adhesion molecule-1 (VCAM-1). The structure/activity relation ship of the LDV sequence is discussed and related to the recently publ ished X-ray structure of VCAM-1. The relevance of the work to the desi gn of antiinflammatory drugs is discussed.