INHIBITION OF HOMOTYPIC ADHESION OF T-CELLS - SECONDARY STRUCTURE OF AN ICAM-1-DERIVED CYCLIC PEPTIDE

The objective of this study was to elucidate the solution conformation of cyclo-(1,12) ro2-Ser3-Lys4-Va15-Ile6-Leu7-Pro8-Arg9-Gly11-Cys12 (1 ) derived from the intercellular adhesion molecule-1 (ICAM-1). Cyclic peptide 1 inhibits homotypic adhesion of T-cells (Molt-3) mediated by ICAM-1 and the leukocyte function-associated antigen-1 (LFA-1) on the surface of T-cells. Cyclic peptide 1 is more potent than is the linear peptide r3-Lys4-Val5-Ile6-Leu7-Pro8-Arg9-Gly10-Gly11-Cys12 (2) in inh ibiting homotypic adhesion. The difference in biological activity of p eptides 1 and 2 may be due to the more stable conformation of cyclic p eptide 1 compared to linear peptide 2 or because cyclization prevents the peptide from adopting non-productive conformation. Therefore, conf ormational studies of cyclic peptide 1 will give a better understandin g of its biological active conformation. The conformational studies of cyclic peptide 1 were done by NMR, CD and molecular dynamics simulati ons. NMR studies indicated that the major conformation of cyclic pepti de 1 contained trans-configuration at both X-Pro peptide bonds. Type I beta-turns at Lys4-Val15-Ile6-Leu7 and Leu7-Pro8-Arg9-Gly10 were foun d in cyclic peptide 1. The C- and N-terminal regions of this peptide w ere stabilized by antiparallel beta-sheet-like structure with the pres ence of intramolecular hydrogen bonds. The overall structure of this p eptide exposed the hydrophobic side chains on one face of the molecule and the hydrophilic side chains on the other. (C) Munksgaard 1997.