Lee Han Siean, Postan Michael, Song Angela, Clark Richard J, Bathgate Ross A D, Haugaard-Kedström Linda M, Rosengren K Johan
Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia.
Florey Department of Neuroscience and Mental Health, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia.
Front Chem. 2020 Feb 18;8:87. doi: 10.3389/fchem.2020.00087. eCollection 2020.
Relaxin-3 is a neuropeptide with important roles in metabolism, arousal, learning and memory. Its cognate receptor is the relaxin family peptide-3 (RXFP3) receptor. Relaxin-3 agonist and antagonist analogs have been shown to be able to modulate food intake in rodent models. The relaxin-3 B-chain is sufficient for receptor interactions, however, in the absence of a structural support, linear relaxin-3 B-chain analogs are rapidly degraded and thus unsuitable as drug leads. In this study, two different disulfide-stabilized scaffolds were used for grafting of important relaxin-3 B-chain residues to improve structure and stability. The use of both Trypsin inhibitor (VhTI) and apamin grafting resulted in agonist and antagonist analogs with improved helicity. VhTI grafted peptides showed poor binding and low potency at RXFP3, on the other hand, apamin variants retained significant activity. These variants also showed improved half-life in serum from ~5 min to >6 h, and thus are promising RXFP3 specific pharmacological tools and drug leads for neuropharmacological diseases.
松弛素-3是一种神经肽，在新陈代谢、觉醒、学习和记忆中发挥着重要作用。其同源受体是松弛素家族肽-3（RXFP3）受体。在啮齿动物模型中，松弛素-3激动剂和拮抗剂类似物已被证明能够调节食物摄入量。松弛素-3 B链足以进行受体相互作用，然而，在缺乏结构支撑的情况下，线性松弛素-3 B链类似物会迅速降解，因此不适合作为药物先导物。在本研究中，使用了两种不同的二硫键稳定支架来嫁接重要的松弛素-3 B链残基，以改善结构和稳定性。使用胰蛋白酶抑制剂（VhTI）和蜂毒明肽嫁接均产生了螺旋度提高的激动剂和拮抗剂类似物。另一方面，VhTI嫁接肽在RXFP3上显示出较差的结合力和低效价，而蜂毒明肽变体保留了显著的活性。这些变体在血清中的半衰期也从约5分钟延长至>6小时，因此是用于神经药理学疾病的有前景的RXFP3特异性药理学工具和药物先导物。
