Utilization of Chemical Proteomics in Covalent Drug Discovery

Abstract

Recent advances in genetic engineering technologies represented by genome editing have been identifying numerous attractive therapeutic protein targets. In this context, expanding the range of targetable proteins by drugs has had increased value. However, it still remains a substantial gap between the discovery of disease-associated proteins and their practical draggability. Development of covalent drugs have long been avoided due to concerns about off-target toxicity. However, they have recently gained increasing attention in terms of their advantages on target selectivity, prolonged pharmacological effects, and efficacy against resistance-associated mutations. Importantly, covalent drugs have also shown promise in targeting proteins, which were previously sought to be undruggable by non-covalent small molecules. These features highlight their renewed values in drug discovery.

In this review, we introduce the pivotal role of chemical proteomics analysis in contemporary covalent drug discovery and development, with a particular focus on its utility and experimental design.