An Unusual Conformation of 纬-Melanocyte-Stimulating Hormone Analogues Leads to a Selective Human Melanocortin 1 Receptor Antagonist for Targeting Melanoma Cells

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• 作者：Minying Cai ; Magda Stankova ; Dhanasekaran Muthu ; Alexander Mayorov ; Zhehui Yang ; Devendra Trivedi ; Christopher Cabello ; Victor J. Hruby
• 刊名：Biochemistry
• 出版年：2013
• 出版时间：January 29, 2013
• 年：2013
• 卷：52
• 期：4
• 页码：752-764
• 全文大小：580K
• 年卷期：v.52,no.4(January 29, 2013)
• ISSN：1520-4995

文摘

纬-MSH (纬-melanocyte-stimulating hormone, H-Tyr-Val-Met-Gly-His-Phe-Arg-Trp-Asp-Arg-Phe-Gly-OH), with its exquisite specificity and potency, has recently created much excitement as a drug lead. However, this peptide is like most peptides susceptible to proteolysis in vivo, which potentially decreases its beneficial activities. In our continued effort to design a proteolytically stable ligand with specific receptor binding, we have engineered peptides by cyclizing 纬-MSH using a thioether bridge. A number of novel cyclic truncated 纬-MSH analogues were designed and synthesized, in which a thioether bridge was incorporated between a cysteine side chain and an N-terminal bromoacyl group. One of these peptides, cyclo-[(CH<sub>2sub>)<sub>3sub>CO-Gly<sup>1sup>-His<sup>2sup>-<span class="smallcaps">dspan>-Phe<sup>3sup>-Arg<sup>4sup>-<span class="smallcaps">dspan>-Trp<sup>5sup>-Cys(S-)<sup>6sup>]-Asp<sup>7sup>-Arg<sup>8sup>-Phe<sup>9sup>-Gly<sup>10sup>-NH<sub>2sub>, demonstrated potent antagonist activity and receptor selectivity for the human melanocortin 1 receptor (hMC1R) (IC<sub>50sub> = 17 nM). This novel peptide is the most selective antagonist for the hMC1R to date. Further pharmacological studies have shown that this peptide can specifically target melanoma cells. The nuclear magnetic resonance analysis of this peptide in a membrane-like environment revealed a new turn structure, specific to the hMC1R antagonist, at the C-terminus, where the side chain and backbone conformation of <span class="smallcaps">dspan>-Trp<sup>5sup> and Phe<sup>9sup> of the peptide contribute to hMC1R selectivity. Cyclization strategies represent an approach for stabilizing bioactive peptides while keeping their full potencies and should boost applications of peptide-based drugs in human medicine.