Activity and conformation of a cyclic heptapeptide possessing the message sequence His-Phe-Arg-Trp of α-melanotropin

Abstract

α-Melanotropin (α-MSH, i.e. α-melanocyte stimulating hormone), tridecapeptide (Ac-Ser 1-Tyr-Ser-Met-G1u 5-His-Phe-Arg-Trp-Gly 10-Lys-Pro-Val 13-NH 2), has been extensively studied to understand structure–activity relationships. The core sequence (His-Phe-Arg-Trp) is conserved in several species and is considered as the primary active site or ‘message sequence’. Attempts have been made to design conformationally constrained cyclic analogs containing the message sequence to improve the activity. We had earlier reported that the cyclic analog—cyclo[Gly-His- d-Phe-Arg-Trp-Gly], a 18 membered ring system with two fused β-turn structure, was less active than the corresponding linear peptide. It was suggested that ring size could be an important parameter in the activity of cyclic melanotropic analogs. To investigate the effect of ring size on biological activity, a cyclic heptapeptide, cyclo[Nle 1-Gly-His- d-Phe-Arg 5-Trp-Gly 7], with 21 member ring system was synthesized. This peptide has three orders of magnitude higher biological activity than the cyclic hexapeptide. The conformational study of this cyclic heptapeptide in DMSO-d 6 by NMR and molecular dynamics simulations reveals a structure with two fused β-turns running across the residues d-Phe 4-Gly 7 (Type I) and Gly 7-His 3 (Type II). These findings confirm that stabilization of β-turns and a relatively larger ring size are essential determinants of activity for cyclic α-MSH analogs.