Overview of recent strategic advances in antiviral covalent inhibitors.

Targeted covalent inhibitors (TCIs) have emerged as a promising antiviral modality, functioning through irreversible or reversible modification of conserved nucleophilic residues within essential viral proteins. These agents are increasingly recognized in antiviral drug discovery due to their potential to achieve enhanced target engagement and prolonged pharmacological effects when appropriately designed, thereby addressing limitations of traditional inhibitors such as rapid resistance development and suboptimal efficacy arising from insufficient binding durability. This review summarizes strategic frameworks for antiviral covalent inhibitor development, highlighting seminal and field-defining reports as well as recent advances. It provides a systematic overview of progress in high-throughput screening, mechanistic studies, and the integration of computational chemistry with artificial intelligence, thereby offering insights into the rational design and discovery of next-generation covalent antivirals.