Mutual leveraging of proximity effects and click chemistry in chemical biology

Abstract

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.

Ligation to Scavenging Strategy Enables On-Demand Termination of Targeted Protein Degradation

“…In the last two decades, the development of bioorthogonal reactions has seen significant advances. − In 2008, the Fox and Weissleder lab reported the inverse electron demand Diels–Alder (IEDDA) reaction with strained alkenes as fast bioorthogonal reactions for in vivo click chemistry. , (Figure D) This type of reaction occurring between 1,2,4,5-tetrazines (Tz) and trans-cyclooctenes (TCO) is one of the fastest known click reactions with second-order rate constants of up to 3.3 × 10 6 M –1 ·s –1 . It is therefore not surprising that the tetrazine ligation has been increasingly used in biomedical research. ,,− …”

Click Chemistry: Reaction Rates and Their Suitability for Biomedical Applications

“…For instance, at initial concentrations of 10 μM for both reactants, 100 M −1 s −1 is calculated to have a half-life of approximately 0.28 h. 102 Moderate reaction rates, ranging from 1 to 30 M −1 s −1 , correspond to a half-life between 1 to 28 h, when using the same initial concentration of 10 μM. 102 Slow kinetic reactions, characterized by values under 1 M −1 s −1 , 27 lead to reaction completion over extended time periods, ranging from days to years. For initial concentrations of 10 μM for both reactants, a rate of 1 M −1 s −1 yields a half-life of around 28 h. 102 In this section of the review, detailed analysis of click chemistry applications, with respect to reported reaction rates, will be discussed for biomedical applications, including cancer therapy, pre-targeting approaches, and imaging probe implementation.…”

A Bioorthogonal Decaging Chemistry of N-Oxide and Silylborane for Prodrug Activation both In Vitro and In Vivo

“…Click chemistry has substantially facilitated research at the interface of chemistry and biology, − and the Nobel Prize in Chemistry of 2022 was awarded to the three scientists (Carolyn R. Bertozzi, Morten Meldal, and K. Barry Sharpless) for their pioneering work in click chemistry and bioorthogonal chemistry. Initially, click chemistry was widely known for its easy bond-formation nature and has been broadly applied to the labeling of bio-macromolecules in the biological milieu without disrupting the native biochemical process. − ,, In recent years, the bond-cleavage nature of some specific click reactions has aroused intensive research interest due to its potentially versatile applications in chemical biology, drug development, and drug delivery. − In the context of drug delivery, the activation of the drug payload by a click reaction (known as a bioorthogonal prodrug or “click-and-release” strategy) exhibited multifaceted advantages over the traditional one.…”