Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Divisions of Renal Medicine and Engineering, Brigham and Women's Hospital, Boston, MA 02115, USA.
Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Cell Chem Biol. 2021 Jul 15;28(7):1081-1089. doi: 10.1016/j.chembiol.2021.06.005.
Nature takes advantage of induced proximity to perform various functions. Taking inspiration from nature, we can also trigger desired biological processes using bifunctional small molecules that artificially induce proximity. For example, bifunctional small molecules have been designed to trigger the ubiquitin-dependent proteasomal degradation of intracellular proteins. Now, recent classes of bifunctional compounds have been developed to degrade extracellular targets, membrane proteins, damaged organelles, and RNA by recruiting alternative degradation pathways. In addition to inducing degradation, bifunctional modalities can change phosphorylation and glycosylation states to evoke a biological response. In this review, we highlight recent advances in these innovative classes of compounds that build on a rich history of chemical inducers of dimerization. We anticipate that more bifunctional molecules, which induce or remove posttranslational modifications, to endow neo-functionalities will emerge.
自然界利用诱导邻近性来执行各种功能。受自然启发，我们也可以使用人工诱导邻近性的双功能小分子来触发所需的生物过程。例如，已经设计了双功能小分子来触发细胞内蛋白质的泛素依赖性蛋白酶体降解。现在，已经开发出了最近几类双功能化合物，通过招募替代降解途径来降解细胞外靶标、膜蛋白、受损细胞器和 RNA。除了诱导降解外，双功能模式还可以改变磷酸化和糖基化状态，引发生物学反应。在这篇综述中，我们强调了这些创新类化合物的最新进展，这些化合物建立在丰富的二聚化化学诱导剂历史之上。我们预计，将出现更多诱导或去除翻译后修饰的双功能分子，从而赋予新功能。
