Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, MA, USA.
Nat Chem Biol. 2020 Apr;16(4):369-378. doi: 10.1038/s41589-020-0469-1. Epub 2020 Mar 20.
Nature uses a variety of tools to mediate the flow of information in cells, many of which control distances between key biomacromolecules. Researchers have thus generated compounds whose activities stem from interactions with two (or more) proteins simultaneously. In this Perspective, we describe how these 'bifunctional' small molecules facilitate the study of an increasingly wide range of complex biological phenomena and enable the drugging of otherwise challenging therapeutic targets and processes. Despite their structural and functional differences, all bifunctional molecules employ Nature's strategy of altering interactomes and inducing proximity to modulate biology. They therefore exhibit a shared set of chemical and biophysical principles that have not yet been appreciated fully. By highlighting these commonalities-and their wide-ranging consequences-we hope to chip away at the artificial barriers that threaten to constrain this interdisciplinary field. Doing so promises to yield remarkable benefits for biological research and therapeutics discovery.
自然界使用多种工具来调节细胞内的信息流，其中许多工具控制关键生物大分子之间的距离。因此，研究人员生成了一些化合物，其活性源于与两个（或更多）蛋白质同时相互作用。在本观点中，我们描述了这些“双功能”小分子如何促进对越来越广泛的复杂生物现象的研究，并使原本具有挑战性的治疗靶点和过程得以用药。尽管它们的结构和功能不同，但所有双功能分子都采用了改变蛋白质组并诱导接近以调节生物学的策略。因此，它们表现出一组尚未被充分认识的共同的化学和物理原理。通过强调这些共性及其广泛的后果，我们希望消除威胁限制这个跨学科领域的人为障碍。这样做有望为生物研究和治疗发现带来显著的益处。
