Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
School of Pharmacy, Second Military Medical University, Shanghai, China.
Adv Exp Med Biol. 2019;1163:313-334. doi: 10.1007/978-981-13-8719-7_13.
Protein-protein interactions (PPIs) represent promising drug targets of broad-spectrum therapeutic interests due to their critical implications in both health and disease circumstances. Hence, they are widely accepted as the Holy Grail of drug development. Historically, PPIs were rendered "undruggable" for their large, flat, and pocket-less structures. Current attempts to drug these "intractable" targets include orthosteric and allosteric methodologies. Previous efforts employing orthosteric approaches like protein therapeutics and orthosteric small molecules frequently suffered from poor performance caused by the difficulties in directly targeting PPI interfaces. As structural biology progresses rapidly, allosteric modulators, which direct to the allosteric regulatory sites remote to the PPI surfaces, have gradually established as a potential solution. Allosteric pockets are topologically distal from the PPI orthosteric sites, and their ligands do not need to compete with the PPI partners, which helps to improve the physiochemical and pharmacological properties of allosteric PPI modulators. Thus, exploiting allostery to tailor PPIs is regarded as a tempting strategy in future PPI drug discovery. Here, we provide a comprehensive review of our representative achievements along the way we utilize allosteric effects to tame the difficult PPI systems into druggable targets. Importantly, we provide an in-depth mechanistic analysis of this success, which will be instructive to future related lead optimizations and drug design. Finally, we discuss the current challenges in allosteric PPI drug discovery. Their solutions as well as future perspectives are also presented.
蛋白质-蛋白质相互作用 (PPIs) 因其在健康和疾病情况下的关键意义，代表了具有广泛治疗兴趣的广谱药物靶点，具有广阔的前景。因此，它们被广泛认为是药物开发的圣杯。历史上，由于其大而平坦且没有口袋的结构，PPIs 被认为是“不可成药的”。目前，针对这些“难治”靶点的药物开发尝试包括变构和变构两种方法。以前采用变构方法，如蛋白质治疗药物和变构小分子，由于直接靶向 PPI 界面的困难，经常因性能不佳而受挫。随着结构生物学的快速发展，变构调节剂逐渐成为一种潜在的解决方案，它可以靶向远离 PPI 表面的变构调节位点。变构口袋在拓扑上远离 PPI 的变构结合位点，其配体不需要与 PPI 配体竞争，这有助于改善变构 PPI 调节剂的物理化学和药理学特性。因此，利用变构来调节 PPI 被认为是未来 PPI 药物发现的诱人策略。在这里，我们全面回顾了我们在利用变构效应将困难的 PPI 系统驯服为可成药靶标的过程中取得的代表性成就。重要的是，我们对这一成功进行了深入的机制分析，这将对未来相关先导化合物优化和药物设计具有指导意义。最后，我们讨论了变构 PPI 药物发现中的当前挑战。还提出了它们的解决方案和未来展望。
