Recent Advances in Covalent Drug Discovery

In spite of the increasing number of biologics license applications, the development of covalent inhibitors is still a growing field within drug discovery. The successful approval of some covalent protein kinase inhibitors, such as ibrutinib (BTK covalent inhibitor) and dacomitinib (EGFR covalent inhibitor), and the very recent discovery of covalent inhibitors for viral proteases, such as boceprevir, narlaprevir, and nirmatrelvir, represent a new milestone in covalent drug development. Generally, the formation of covalent bonds that target proteins can offer drugs diverse advantages in terms of target selectivity, drug resistance, and administration concentration. The most important factor for covalent inhibitors is the electrophile (warhead), which dictates selectivity, reactivity, and the type of protein binding (i.e., reversible or irreversible) and can be modified/optimized through rational designs. Furthermore, covalent inhibitors are becoming more and more common in proteolysis, targeting chimeras (PROTACs) for degrading proteins, including those that are currently considered to be 'undruggable'. The aim of this review is to highlight the current state of covalent inhibitor development, including a short historical overview and some examples of applications of PROTAC technologies and treatment of the SARS-CoV-2 virus.

Automated summary

Despite the increasing number of biologics license applications, the development of covalent inhibitors remains a growing field in drug discovery. The successful approval of certain covalent protein kinase inhibitors and the recent discovery of covalent inhibitors for viral proteases represent advancements in covalent drug development. Covalent bonds targeting proteins offer advantages in target selectivity, drug resistance, and administration concentration. The electrophile (warhead) is a crucial factor for covalent inhibitors, dictating selectivity and reactivity, and can be modified through rational designs. Covalent inhibitors are also finding applications in protein degradation and targeting chimeras (PROTACs) for 'undruggable' proteins, as well as in the treatment of SARS-CoV-2.