Unifying principles of bifunctional, proximity-inducing small molecules
Unifying principles of bifunctional, proximity-inducing small molecules
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DOI：
10.1038/s41589-020-0469-1
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发表时间：
2020-04-01
影响因子：
14.8
通讯作者：
Schreiber, Stuart L.
中科院分区：
文献类型：
--
作者：
Gerry, Christopher J.;Schreiber, Stuart L.
这一观点描述了所有双官能团、邻近诱导的小分子共同的化学和生物物理原理。它还讨论了它们被低估的化学结构和生物机制的多样性。大自然使用各种工具来调节细胞中的信息流，其中许多工具控制着关键生物大分子之间的距离。因此，研究人员产生的化合物的活性源于同时与两种(或更多)蛋白质的相互作用。在这一角度下，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能够进行药物治疗。尽管它们的结构和功能不同，但所有的双功能分子都使用大自然改变相互作用和诱导接近的策略来调节生物学。因此，它们展示了一套尚未被充分认识的共同的化学和生物物理原理。通过强调这些共性及其广泛的后果，我们希望消除可能限制这一跨学科领域的人为障碍。这样做有望为生物研究和疗法发现带来显著的好处。
This Perspective describes the chemical and biophysical principles common to all bifunctional, proximity-inducing small molecules. It also discusses the underappreciated diversity of their chemical structures and biological mechanisms.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.