Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
Curr Top Med Chem. 2019;19(21):1872-1876. doi: 10.2174/1568026619666191011163410.
PPIs are involved in diverse biochemical events and perform their functions through the formation of protein-protein complexes or PPI networks. The large and flat interacting surfaces of PPIs make discovery of small-molecule modulators a challenging task. New strategies and more effective chemical technologies are needed to facilitate the development of PPIs small-molecule inhibitors. Covalent modification of a nucleophilic residue located proximally to the immediate vicinity of PPIs can overcome the disadvantages of large interacting surfaces and provides high-affinity inhibitors with increased duration of action and prolonged target modulation. On the other hand, covalent inhibitors that target non-conserved protein residues demonstrate improved selectivity over related protein family members. Herein, we highlight the latest progress of small-molecule covalent PPIs inhibitors and hope to shed light on future PPIs inhibitor design and development. The relevant challenges and opportunities are also discussed.
PPIs 参与多种生化事件，并通过形成蛋白质-蛋白质复合物或 PPI 网络来发挥其功能。PPI 的大而平坦的相互作用表面使得发现小分子调节剂成为一项具有挑战性的任务。需要新的策略和更有效的化学技术来促进 PPI 小分子抑制剂的开发。将亲核残基共价修饰到 PPI 的紧邻位置附近，可以克服大相互作用表面的缺点，并提供具有更高亲和力、更长作用时间和更长靶标调制的抑制剂。另一方面，靶向非保守蛋白质残基的共价抑制剂在相关蛋白质家族成员中表现出更高的选择性。本文重点介绍了小分子共价 PPI 抑制剂的最新进展，并希望为未来的 PPI 抑制剂设计和开发提供启示。还讨论了相关的挑战和机遇。
