Peptide and small molecules rescue the functional activity and agonist potency of dysfunctional human melanocortin-4 receptor polymorphisms.
Xiang. Zhimin Z; Pogozheva. Irina D ID; Sorenson. Nicholas B NB; Wilczynski. Andrzej M AM; Holder. Jerry Ryan JR; Litherland. Sally A SA; Millard. William J WJ; Mosberg. Henry I HI; Haskell-Luevano. Carrie C
Key Findings
- 13 MC4R polymorphisms show reduced response to the natural hormone
- NDP‑MSH, MTII, AMW3‑130, THIQ and AMW3‑106 regain nanomolar‑level activation of these mutant receptors
- These ligands could help study MC4R‑related weight regulation and may guide future drug development
Practical Outcomes
- While the findings hint at future therapies for MC4R‑related obesity, the identified ligands are not commercially available or proven safe for self‑administration. Biohackers should view this as early‑stage science rather than a ready‑to‑use protocol.
Summary
The paper shows that some experimental peptides and small molecules can restore activity of mutated MC4R receptors that are linked to obesity, but these compounds are still research tools and not approved for personal use.
Abstract
The melanocortin pathway, specifically the melanocortin-4 receptor and the cognate endogenous agonist and antagonist ligands, have been strongly implicated in the regulation of energy homeostasis and satiety. Genetic studies of morbidly obese human patients and normal weight control patients have resulted in the discovery of over 70 human melanocortin-4 receptor (MC4R) polymorphisms observed as both heterozygous and homozygous forms. A number of laboratories have been studying these hMC4R polymorphisms attempting to understand the molecular mechanism(s) that might explain the obese human phenotype. Herein, we have studied 13 polymorphic hMC4Rs that have been identified to possess statistically significant decreased endogenous agonist potency with synthetic peptides and small molecules attempting 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), and the 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. These studies resulted in the NDP-MSH, MTII, AMW3-130, THIQ, and AMW3-106 ligands possessing nanomolar to subnanomolar agonist potency at the hMC4R polymorphisms examined in this study. Thus, these ligands could generically rescue the potency and stimulatory response of the abnormally functioning hMC4Rs studied and may provide tools to further clarify the molecular mechanism(s) involving these receptor modifications.
Study Information
pubmed
2007
2007-06-23T00:00:00.000Z
10.1021/bi7007382