Winget Marshall D, Ericson Mark D, Freeman Katie T, Haskell-Luevano Carrie
Department of Medicinal Chemistry & Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, United States.
ACS Med Chem Lett. 2019 Jul 2;11(3):272-277. doi: 10.1021/acsmedchemlett.9b00198. eCollection 2020 Mar 12.
The melanocortin receptors are stimulated by agonists (α-MSH, β-MSH, γ-MSH, and ACTH) processed from the proopiomelanocortin (POMC) gene transcript and possess a common His-Phe-Arg-Trp tetrapeptide sequence critical for receptor activation. Deficiency in POMC signaling in humans is associated with adrenal insufficiency, altered pigmentation, and rapid, early onset weight gain. Herein, 12 single nucleotide polymorphisms (SNPs) deposited into the Variation Viewer database within the His-Phe-Arg-Trp sequences of ACTH/α-MSH, β-MSH, and γ-MSH were substituted into tetrapeptide scaffolds to examine the signaling effects of these polymorphisms at the cloned melanocortin receptors. Every polymorphism decreased agonist potency and/or efficacy at the melanocortin receptors assayed, indicating that polymorphisms within the signaling sequence of POMC-derived agonists negatively impacts receptor activation. Future work to incorporate these substitutions into the full-length POMC agonists would confirm these findings, identifying new patient populations that might benefit from therapeutic regiments to treat POMC-deficient signaling.
促黑素细胞激素受体可被源自阿黑皮素原（POMC）基因转录本的激动剂（α-促黑素细胞激素、β-促黑素细胞激素、γ-促黑素细胞激素和促肾上腺皮质激素）激活，且拥有对受体激活至关重要的共同的组氨酸-苯丙氨酸-精氨酸-色氨酸四肽序列。人类POMC信号传导缺陷与肾上腺功能不全、色素沉着改变以及迅速、早发性体重增加有关。在此，将存入变异查看器数据库的位于促肾上腺皮质激素/α-促黑素细胞激素、β-促黑素细胞激素和γ-促黑素细胞激素的组氨酸-苯丙氨酸-精氨酸-色氨酸序列内的12个单核苷酸多态性（SNP）替换到四肽支架中，以检测这些多态性在克隆的促黑素细胞激素受体处的信号传导效应。在所检测的促黑素细胞激素受体上，每个多态性均降低了激动剂的效力和/或效能，表明POMC衍生激动剂信号序列内的多态性对受体激活产生负面影响。将这些替换纳入全长POMC激动剂的未来研究将证实这些发现，从而确定可能受益于治疗POMC缺陷信号传导治疗方案的新患者群体。
