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Single Nucleotide Polymorphisms in the Melanocortin His-Phe-Arg-Trp Sequences Decrease Tetrapeptide Potency and Efficacy
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-07-24 , DOI: 10.1021/acsmedchemlett.9b00198 Marshall D. Winget 1 , Mark D. Ericson 1 , Katie T. Freeman 1 , Carrie Haskell-Luevano 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-07-24 , DOI: 10.1021/acsmedchemlett.9b00198 Marshall D. Winget 1 , Mark D. Ericson 1 , Katie T. Freeman 1 , Carrie Haskell-Luevano 1
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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 in vitro 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.
中文翻译：
黑皮质素His-Phe-Arg-Trp序列中的单个核苷酸多态性降低四肽效能和功效。
黑色素皮质激素受体受从proopiomelanocortin（POMC）基因转录物加工的激动剂（α-MSH，β-MSH，γ-MSH和ACTH）刺激，并具有共同的对受体激活至关重要的His-Phe-Arg-Trp四肽序列。人体内POMC信号的缺乏与肾上腺功能不全，色素沉着改变以及体重的快速，早期发作有关。在此，将ACTH /α-MSH，β-MSH和γ-MSH的His-Phe-Arg-Trp序列内存放在Variation Viewer数据库中的12个单核苷酸多态性（SNP）替换为四肽支架，以进行体外检查这些多态性对克隆的黑皮质素受体的信号转导作用。每种多态性均降低了所测定的黑皮质素受体的激动剂效价和/或功效，表明POMC衍生的激动剂信号序列内的多态性会对受体激活产生负面影响。将这些替代物整合到全长POMC激动剂中的未来工作将证实这些发现，从而确定可能从治疗方案中获益的新患者群体，以治疗POMC缺陷型信号传导。
更新日期：2019-11-18
中文翻译：
黑皮质素His-Phe-Arg-Trp序列中的单个核苷酸多态性降低四肽效能和功效。
黑色素皮质激素受体受从proopiomelanocortin（POMC）基因转录物加工的激动剂（α-MSH，β-MSH，γ-MSH和ACTH）刺激，并具有共同的对受体激活至关重要的His-Phe-Arg-Trp四肽序列。人体内POMC信号的缺乏与肾上腺功能不全，色素沉着改变以及体重的快速，早期发作有关。在此，将ACTH /α-MSH，β-MSH和γ-MSH的His-Phe-Arg-Trp序列内存放在Variation Viewer数据库中的12个单核苷酸多态性（SNP）替换为四肽支架，以进行体外检查这些多态性对克隆的黑皮质素受体的信号转导作用。每种多态性均降低了所测定的黑皮质素受体的激动剂效价和/或功效，表明POMC衍生的激动剂信号序列内的多态性会对受体激活产生负面影响。将这些替代物整合到全长POMC激动剂中的未来工作将证实这些发现，从而确定可能从治疗方案中获益的新患者群体，以治疗POMC缺陷型信号传导。
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