Effect of helix-promoting strategies on the biological activity of novel analogues of the B-chain of INSL3.
Insulin-like 3 (INSL3) is a novel circulating peptide hormone that is produced by testicular Leydig cells and ovarian thecal and luteal cells. In males, INSL3 is responsible for testicular descent during foetal life and suppresses germ cell apoptosis in adult males, whereas in females, it causes oocyte maturation. Antagonists of INSL3 thus have significant potential clinical application as contraceptives in both males and females. Previous work has shown that the INSL3 receptor binding region is largely confined to the B-chain central alpha-helix of the hormone and a conformationally constrained analogue of this has modest receptor binding and INSL3 antagonist activity. In the present study, we have employed and evaluated several approaches for increasing the alpha-helicity of this peptide in order to better present the key receptor binding residues and increase its affinity for the receptor. Analogues of INSL3 with higher alpha-helicity generally had higher receptor binding affinity although other structural considerations limit their effectiveness.
Shabanpoor
Fazel
F
Howard Florey Institute, University of Melbourne, Melbourne, VIC, 3010, Australia.
Hughes
Richard A
RA
Zhang
Suode
S
Bathgate
Ross A D
RA
Layfield
Sharon
S
Hossain
Mohammed Akhter
MA
Tregear
Geoffrey W
GW
Separovic
Frances
F
Wade
John D
JD
D000595:Amino Acid Sequence; D001665:Binding Sites; D002460:Cell Line; D006801:Humans; D007328:Insulin / Q000819:agonists* / Q000138:chemical synthesis / Q000737:chemistry; D018969:Insulin-Like Growth Factor Binding Proteins / Q000737:chemistry; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011506:Proteins / Q000819:agonists* / Q000138:chemical synthesis / Q000737:chemistry
D007328:Insulin; D018969:Insulin-Like Growth Factor Binding Proteins; C084797:Leydig insulin-like protein; D011506:Proteins