Advances in Antiviral Drug Development Targeting Viral Proteases.

Viral proteases are critical targets in antiviral drug development due to their essential role in the viral lifecycle and high conservation across viral strains. This review summarizes the recent progress of antiviral drugs based on protease structures, with a focus on the structural characteristics and inhibitor design strategies targeting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Enterovirus 71 (EV71), Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV). Based on the three-dimensional structure of proteases, various types of protease inhibitors such as peptidomimetic, non-peptidic, and natural product-derived inhibitors are discussed. Given the critical challenge of drug resistance in antiviral therapies, we address the mechanisms of protease inhibitor resistance and explore advanced strategies, including allosteric inhibition, dual-target inhibition, and Proteolysis-Targeting Chimeras (PROTAC) to overcome drug resistance. This review also explores the cutting-edge applications of artificial intelligence (AI) for viral protease-based antiviral drug discovery, providing valuable insights for the rational design and development of antiviral drugs.