Zhou Yang, Mowlazadeh Haghighi Saghar, Zoi Ioanna, Sawyer Jonathon R, Hruby Victor J, Cai Minying
Department of Chemistry and Biochemistry, The University of Arizona , Tucson, Arizona 85721, United States.
J Med Chem. 2017 Nov 22;60(22):9320-9329. doi: 10.1021/acs.jmedchem.7b01295. Epub 2017 Nov 13.
Melanoma is a lethal form of skin cancer. Skin pigmentation, which is regulated by the melanocortin 1 receptor (MC1R), is an effective protection against melanoma. However, the endogenous MC1R agonists lack selectivity for the MC1R and thus can have side effects. The use of noncanonical amino acids in previous MC1R ligand development raises safety concerns. Here we report the development of the first potent and selective hMC1R agonist with only canonical amino acids. Using γ-MSH as a template, we developed a peptide, [Leu, Leu, Phe]-γ-MSH-NH (compound 5), which is 16-fold selective for the hMC1R (EC = 4.5 nM) versus other melanocortin receptors. Conformational studies revealed a constrained conformation for this linear peptide. Molecular docking demonstrated a hydrophobic binding pocket for the melanocortin 1 receptor. In vivo pigmentation study shows high potency and short duration. [Leu, Leu, Phe]-γ-MSH-NH is ideal for inducing short-term skin pigmentation without sun for melanoma prevention.
黑色素瘤是一种致命的皮肤癌。由黑皮质素1受体（MC1R）调节的皮肤色素沉着是抵御黑色素瘤的有效保护机制。然而，内源性MC1R激动剂对MC1R缺乏选择性，因此可能会产生副作用。在先前的MC1R配体开发中使用非天然氨基酸引发了安全问题。在此，我们报告了首个仅由天然氨基酸组成的强效且选择性的人MC1R激动剂的开发情况。以γ-促黑素（γ-MSH）为模板，我们开发了一种肽，即[亮氨酸，亮氨酸，苯丙氨酸]-γ-MSH-NH（化合物5），相对于其他黑皮质素受体，它对人MC1R的选择性高16倍（EC = 4.5 nM）。构象研究揭示了这种线性肽的受限构象。分子对接显示黑皮质素1受体存在一个疏水结合口袋。体内色素沉着研究表明其效力高且持续时间短。[亮氨酸，亮氨酸，苯丙氨酸]-γ-MSH-NH是在无阳光照射情况下诱导短期皮肤色素沉着以预防黑色素瘤的理想选择。
