title: Activity and conformation of a cyclic heptapeptide possessing the message sequence His-Phe-Arg-Trp of alpha-melanotropin.
abstract: Alpha-melanotropin (alpha-MSH, i.e. alpha-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 beta-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 beta-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 beta-turns and a relatively larger ring size are essential determinants of activity for cyclic alpha-MSH analogs.
authors.affiliation: Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Mumbai 400098, India.
authors.forename: Prashant
authors.initials: P
authors.lastname: Desai
authors.forename: Mamta
authors.initials: M
authors.lastname: Prachand
authors.forename: Evans
authors.initials: E
authors.lastname: Coutinho
authors.forename: Anil
authors.initials: A
authors.lastname: Saran
authors.forename: J
authors.initials: J
authors.lastname: Bodi
authors.forename: H
authors.initials: H
authors.lastname: Süli-Vargha
mesh_terms: D000818:Animals; D001671:Biochemistry / Q000379:methods; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D000521:alpha-MSH / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D010446:Peptide Fragments; D010456:Peptides, Cyclic; C470029:cyclo(glycyl-histidyl-phenylalanyl-arginyl-tryptophyl-glycyl); D000521:alpha-MSH