Chemistry of Covalent Drugs: Chemical Reactions with Endogenous Proteins in Live Cells

Covalent drugs render potent and durable activity by chemical modification of the endogenous target protein under live cell conditions. To maximize the pharmacological efficay while alleviating the risk of toxicity arising from non-specific off-target reactions, current covalent drug discovery focuses on the development of targeted covalent inhibitors (TCIs). In the design of TCIs, an electrophilic reactive group (warhead) is strategically incorporated onto a reversible ligand of the target protein to facillitate specific covalent engagement. Various aspects of warheads, such as intrinsic reactivity, chemoselectivity, reaction mechanism, and reversibility of the covalent engagement, would affect the target selectivity of TCIs. While covalent targeting of cysteines by acrylamide-type Michael acceptors have been the most successful strategy in covalent drug discovery, a wide array of novel warheads have been devised and tested for designing TCIs in recent years. This review provides an overview of chemistry for selective covalent targeting of endogenous proteins under live cell conditions and its applications in TCI designs.