Nature has the remarkable ability to realize reactions under physiological conditions that normally would require high temperature and other forcing conditions. In doing so, often proximity effects such as simultaneous binding of two reactants in the same pocket and/or strategic positioning of catalytic functional groups are used as ways to achieve otherwise kinetically challenging reactions. Though true biomimicry is challenging, there have been many beautiful examples of how to leverage proximity effects in realizing reactions that otherwise would not readily happen under near-physiological conditions. Along this line, click chemistry is often used to endow proximity effects, and proximity effects are also used to further leverage the facile and bioorthogonal nature of click chemistry. This review brings otherwise seemingly unrelated topics in chemical biology and drug discovery under one unifying theme of mutual leveraging of proximity effects and click chemistry and aims to critically analyze the biomimicry use of such leveraging effects as powerful approaches in chemical biology and drug discovery. We hope that this review demonstrates the power of employing mutual leveraging proximity effects and click chemistry and inspires the development of new strategies that will address unmet needs in chemistry and biology.
Keywords: bioorthogonal chemistry; drug delivery; in-situ click; neighboring group participation; proximity effect.
© 2022 Wiley Periodicals LLC.