Covalent inhibition has seen a resurgence in the last several years. Although long-plagued by concerns of off-target effects due to nonspecific reactions leading to covalent adducts, there has been success in developing covalent inhibitors, especially within the field of anticancer therapy. Covalent inhibitors can have an advantage over noncovalent inhibitors since the formation of a covalent adduct may serve as an additional mode of selectivity due to the intrinsic reactivity of the target protein that is absent in many other proteins. Unfortunately, many covalent inhibitors form irreversible adducts with off-target proteins, which can lead to considerable side-effects. By designing the inhibitor to form reversible covalent adducts, one can leverage competing on/off kinetics in complex formation by taking advantage of the law of mass action. Although covalent adducts do form with off-target proteins, the reversible nature of inhibition prevents accumulation of the off-target adduct, thus limiting side-effects. In this perspective, we outline important characteristics of reversible covalent inhibitors, including examples and a guide for inhibitor development.
A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs. @CovalentMod on Twitter, @covalentmod@mstdn.science on Mastodon, and @covalentmod.bsky.social on BlueSky
Research progress on covalent inhibitors targeting alkaline amino acids
Bing Zhao, Sha Xu, Shiqing Zhou, Xiangru Jiang, Ailin Jiang, Hongrui Lei, Xin Zhai Bioorganic Chemistry, 163, 2025, 108800, https://doi.org...
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Design, synthesis and biological evaluation of the activity-based probes for FGFR covalent inhibitorDandan Zhu, Zijian Zheng, Huixin Huang, Xiaojuan Chen, Shuhong Zhang, Zhuchu Chen, Ting Liu, Guangyu Xu, Ying Fu, Yongheng Chen, European Jo...
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DOI Ansgar Oberheide, Maxime van den Oetelaar, Jakob Scheele, Jan Borggräfe, Semmy Engelen, Michael Sattler, Christian Ottmann, ...
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Yoav Shamir, Nir London bioRxiv 2025.03.19.642201 doi: https://doi.org/10.1101/2025.03.19.642201 Recent years have seen an explosion in the...