The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA.
Nat Rev Drug Discov. 2012 Jan 3;11(1):52-68. doi: 10.1038/nrd3620.
Serine hydrolases perform crucial roles in many biological processes, and several of these enzymes are targets of approved drugs for indications such as type 2 diabetes, Alzheimer's disease and infectious diseases. Despite this, most of the human serine hydrolases (of which there are more than 200) remain poorly characterized with respect to their physiological substrates and functions, and the vast majority lack selective, in vivo-active inhibitors. Here, we review the current state of pharmacology for mammalian serine hydrolases, including marketed drugs, compounds that are under clinical investigation and selective inhibitors emerging from academic probe development efforts. We also highlight recent methodological advances that have accelerated the rate of inhibitor discovery and optimization for serine hydrolases, which we anticipate will aid in their biological characterization and, in some cases, therapeutic validation.
丝氨酸水解酶在许多生物过程中发挥着关键作用，其中一些酶是已批准用于治疗 2 型糖尿病、阿尔茨海默病和传染病等适应症的药物的靶点。尽管如此，大多数人类丝氨酸水解酶（超过 200 种）在其生理底物和功能方面仍未得到充分表征，而且绝大多数缺乏选择性、体内有效的抑制剂。在这里，我们回顾了哺乳动物丝氨酸水解酶的药理学现状，包括市售药物、正在临床研究中的化合物以及从学术探针开发工作中涌现出的选择性抑制剂。我们还强调了最近的方法学进展，这些进展加速了丝氨酸水解酶抑制剂的发现和优化速度，我们预计这将有助于它们的生物学表征，在某些情况下，还将有助于治疗验证。
