Covalent drug – An emerging framework for targeted drug development

Abstract

Drug discovery involving covalent drugs has a rich history dating back to the 20th century. Despite their longevity, concerns about safety have relegated covalent drug development to the periphery of research focus. The emergence of the groundbreaking concept of Targeted Covalent Inhibition (TCI) has catalyzed a renewed emphasis on covalent medications, elevating their status within the field. This review delves into the landscape of covalent inhibitors, comprehensively examining those developed to date and those currently under investigation.Covalent inhibitors are categorized based on their target proteins, simplifying the understanding of their diverse applications. Notable targets include disease-related proteins such as EGFR, BTK, and SARS-COV-2, signifying the broad therapeutic potential of covalent drugs across various medical domains.One of the most significant aspects discussed is the potential of covalent drugs to overcome the drawbacks associated with conventional therapy, contingent upon the effective consideration of toxicity-related factors. These drugs present a range of advantages, including heightened selectivity, the ability to administer lower doses, and the degradation of previously deemed undruggable proteins.The trajectory of covalent drugs appears promising for drug discovery. By targeting different proteins, these compounds hold the potential to provide effective treatment options in the years to come. The comprehensive exploration of covalent drugs in this review not only contributes to our understanding of their historical evolution and contemporary applications but also underscores their importance as a focal point for advancing therapeutic options and addressing the limitations of current treatment modalities.

Keywords

• Covalent drugs
• Targeted covalent inhibition (TCI)
• Disease-related proteins
• Two-step inhibition process
• Toxicity mitigation strategies