Identification of Tetrapeptides from a Mixture Based Positional Scanning Library That Can Restore nM Full Agonist Function of the L106P, I69T, I102S, A219V, C271Y, and C271R Human Melanocortin-4 Polym

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• 作者：Erica M. Haslach ; Huisuo Huang ; Marvin Dirain ; Ginamarie Debevec ; Phaedra Geer ; Radleigh G. Santos ; Marc A. Giulianotti ; Clemencia Pinilla ; Jon R. Appel ; Skye R. Doering ; Michael A. Walters ; Richard A. Houghten ; Carrie Haskell-Luevano
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：June 12, 2014
• 年：2014
• 卷：57
• 期：11
• 页码：4615-4628
• 全文大小：961K
• 年卷期：v.57,no.11(June 12, 2014)
• ISSN：1520-4804

文摘

Human obesity has been linked to genetic factors and single nucleotide polymorphisms (SNPs). Melanocortin-4 receptor (MC4R) SNPs have been associated with up to 6% frequency in morbidly obese children and adults. A potential therapy for individuals possessing such genetic modifications is the identification of molecules that can restore proper receptor signaling and function. These compounds could serve as personalized medications improving quality of life issues as well as alleviating diseases symptoms associated with obesity including type 2 diabetes. Several hMC4 SNP receptors have been pharmacologically characterized in vitro to have a decreased, or a lack of response, to endogenous agonists such as 伪-, 尾-, and 纬₂-melanocyte stimulating hormones (MSH) and adrenocorticotropin hormone (ACTH). Herein we report the use of a mixture based positional scanning combinatorial tetrapeptide library to discover molecules with nM full agonist potency and efficacy to the L106P, I69T, I102S, A219V, C271Y, and C271R hMC4Rs. The most potent compounds at all these hMC4R SNPs include Ac-His-(pI)DPhe-Tic-(pNO₂)DPhe-NH₂, Ac-His-(pCl)DPhe-Tic-(pNO₂)DPhe-NH₂, Ac-His-(pCl)DPhe-Arg-(pI)Phe-NH₂, and Ac-Arg-(pCl)DPhe-Tic-(pNO₂)DPhe-NH₂, revealing new ligand pharmacophore models for melanocortin receptor drug design strategies.