Chemistry perspectives of reversible covalent drugs

Abstract

Reversible covalent drugs present a novel concept in the development of covalent drugs. The reversibility of the drug–protein target conjugation avoids permanently modified proteins, and hence holds promise in reducing the off-target effect as well as the potential immunogenicity of covalent drugs. This chapter presents a quick overview of the currently available reversible covalent drugs, and then focuses on the physical organic chemistry principles underlying the action of reversible covalent drugs. In particular, we rationalize the design and functions of reversible covalent drugs using the terms of binding free energies and the reaction kinetics in forward and backward directions. Finally, we discuss the challenges and future perspectives of reversible covalent drug design. The chemistry perspectives and principles presented in this chapter provide a conceptual framework to guide future efforts to develop novel reversible covalent drugs for a wider collection of proteins.