Peptide and Small Molecules Rescue the Functional Activity and Agonist Potency of Dysfunctional Human Melanocortin-4 Receptor Polymorphisms

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• 作者：Zhimin Xiang ; Irina D. Pogozheva ; Nicholas B. Sorenson ; Andrzej M. Wilczynski ; Jerry Ryan Holder ; Sally A. Litherland ; William J. Millard ; Henry I. Mosberg ; Carrie Haskell-Luevano
• 刊名：Biochemistry
• 出版年：2007
• 出版时间：July 17, 2007
• 年：2007
• 卷：46
• 期：28
• 页码：8273 - 8287
• 全文大小：536K
• 年卷期：v.46,no.28(July 17, 2007)
• ISSN：1520-4995

文摘

The melanocortin pathway, specifically the melanocortin-4 receptor and the cognate endogenousagonist and antagonist ligands, have been strongly implicated in the regulation of energy homeostasisand satiety. Genetic studies of morbidly obese human patients and normal weight control patients haveresulted in the discovery of over 70 human melanocortin-4 receptor (MC4R) polymorphisms observed asboth heterozygous and homozygous forms. A number of laboratories have been studying these hMC4Rpolymorphisms attempting to understand the molecular mechanism(s) that might explain the obese humanphenotype. Herein, we have studied 13 polymorphic hMC4Rs that have been identified to possessstatistically significant decreased endogenous agonist potency with synthetic peptides and small moleculesattempting to identify ligands that can pharmacologically rescue the hMC4R polymorphic agonist response.The ligands examined in this study include NDP-MSH, MTII, Ac-His-DPhe-Arg-Trp-NH₂ (JRH887-9),Ac-Anc-DPhe-Arg-Trp-NH₂ (amino-2-naphtylcarboxylic acid, Anc, JRH420-12), Ac-His-(pI)DPhe-Arg-Trp-NH₂ (JRH322-18), chimeric AGRP-melanocortin based ligands (Tyr-c[Cys-His-DPhe-Arg-Trp-Asn-Ala-Phe-Cys]-Tyr-NH₂, AMW3-130 and Ac-mini-(His-DPhe-Arg-Trp)-hAGRP-NH₂, AMW3-106), andthe small molecules JB25 and THIQ. The hMC4R polymorphisms included in this study are S58C, N97D,I102S, L106P, S127L, T150I, R165Q, R165W, L250Q, G252S, C271Y, Y287Stop, and I301T. Thesestudies resulted in the NDP-MSH, MTII, AMW3-130, THIQ, and AMW3-106 ligands possessing nanomolarto subnanomolar agonist potency at the hMC4R polymorphisms examined in this study. Thus, these ligandscould generically rescue the potency and stimulatory response of the abnormally functioning hMC4Rsstudied and may provide tools to further clarify the molecular mechanism(s) involving these receptormodifications.