Section on Molecular Neuroscience, National Institute of Mental Heath-Intramural Research Program, NIH, Bethesda, MD, USA.
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.
J Neuroendocrinol. 2020 May;32(5):e12844. doi: 10.1111/jne.12844. Epub 2020 Apr 19.
Recently, there has been a resurgence in regulatory peptide science as a result of three converging trends. The first is the increasing population of the drug pipeline with peptide-based therapeutics, mainly in, but not restricted to, incretin-like molecules for treatment of metabolic disorders such as diabetes. The second is the development of genetic and optogenetic tools enabling new insights into how peptides actually function within brain and peripheral circuits to accomplish homeostatic and allostatic regulation. The third is the explosion in defined structures of the G-protein coupled receptors to which most regulatory peptides bind and exert their actions. These trends have closely wedded basic systems biology to drug discovery and development, creating a "two-way street" on which translational advances travel from basic research to the clinic, and, equally importantly, "reverse-translational" information is gathered, about the molecular, cellular and circuit-level mechanisms of action of regulatory peptides, comprising information required for the fine-tuning of drug development through testing in animal models. This review focuses on a small group of 'influential' peptides, including oxytocin, vasopressin, pituitary adenylate cyclase-activating polypeptide, ghrelin, relaxin-3 and glucagon-like peptide-1, and how basic discoveries and their application to therapeutics have intertwined over the past decade.
最近，由于三种趋势的融合，调节肽科学再次兴起。第一种是基于肽的治疗药物在药物管道中的人口不断增加，主要是但不限于肠促胰岛素样分子，用于治疗代谢紊乱，如糖尿病。第二种是遗传和光遗传学工具的发展，使人们能够深入了解肽如何在大脑和外周电路中实际发挥作用，以完成体内平衡和适应调节。第三种是与大多数调节肽结合并发挥作用的 G 蛋白偶联受体的明确结构的爆炸式增长。这些趋势将基础系统生物学与药物发现和开发紧密地结合在一起，形成了一条“双向街”，其中翻译进展从基础研究到临床，同样重要的是，关于调节肽作用的分子、细胞和电路水平机制的“反向翻译”信息被收集，这些信息是通过在动物模型中进行测试来调整药物开发所必需的。这篇综述集中讨论了一小群“有影响力”的肽，包括催产素、血管加压素、垂体腺苷酸环化酶激活肽、胃饥饿素、松弛素-3 和胰高血糖素样肽-1，以及基础发现及其在治疗学中的应用如何在过去十年中交织在一起。
