Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia; Department of Biochemistry & Molecular Biology, The University of Melbourne, Victoria, Australia.
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia.
Pharmacol Ther. 2018 Jul;187:114-132. doi: 10.1016/j.pharmthera.2018.02.008. Epub 2018 Feb 17.
The peptide relaxin was first identified as an important circulating hormone during pregnancy over 90 years ago. Research over many years defined the numerous biological roles that relaxin plays throughout pregnancy in many mammalian species. These important biological actions have led to the testing of relaxin as a therapeutic agent for a number of indications. The discovery of the relaxin receptor, RXFP1, in 2002 facilitated the better understanding of the cellular targets of relaxin, its mechanism of action and enabled the development of relaxin mimetics and screening for small molecule agonists. Additionally, the rapid expansion of the genome databases and bioinformatics tools has significantly advanced our understanding of the evolution of the relaxin/RXFP1 signaling system. It is now clear that the relaxin-RXFP1 signaling axis is far more ancient than previously appreciated with important roles for invertebrate relaxin-like peptides in reproductive and non-reproductive functions. This review summarizes these advances as well as developments in drug targeting of RXFP1. Hence the complex mode of activation of RXFP1 is discussed as is the discovery and development of a peptide mimetic and small molecule agonist. Detailed signaling studies are summarized which highlight the cell specific signaling of a peptide mimetic and biased signaling of a small molecule agonist. These studies highlight the complexities of targeting peptide GPCRs such as RXFP1.
松弛肽最初于 90 多年前被鉴定为妊娠期间的一种重要循环激素。多年的研究定义了松弛肽在许多哺乳动物物种妊娠期间发挥的众多生物学作用。这些重要的生物学作用促使人们将松弛肽作为多种适应症的治疗剂进行测试。2002 年，松弛素受体 RXFP1 的发现促进了人们对松弛素细胞靶点、作用机制的更好理解，并使松弛素模拟物的开发和小分子激动剂的筛选成为可能。此外，基因组数据库和生物信息学工具的快速扩展极大地促进了我们对松弛素/RXFP1 信号系统进化的理解。现在很清楚，松弛素-RXFP1 信号轴比以前想象的要古老得多，无脊椎动物松弛素样肽在生殖和非生殖功能中起着重要作用。本文综述了这些进展以及 RXFP1 药物靶向的发展。因此，讨论了 RXFP1 的复杂激活模式，以及肽模拟物和小分子激动剂的发现和开发。总结了详细的信号转导研究，突出了肽模拟物的细胞特异性信号转导和小分子激动剂的偏向信号转导。这些研究强调了针对 RXFP1 等肽 GPCR 的靶向的复杂性。
