From 2020 to 2025: Comprehensive review Decoding novel structural inhibitors for Mpro of SARS-CoV-2.

While the immediate global threat of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has subsided, the virus remains a persistent cause of regional outbreaks and public health concerns. The main protease (Mpro), essential for viral polyprotein processing and replication, remains one of the most validated and strategically important antiviral targets. In this comprehensive review, we critically evaluate the landscape of Mpro inhibitor development from 2020 to 2025, encompassing four key categories: peptidomimetic inhibitors, non-peptide small molecules, natural product-derived compounds, and proteolysis-targeting chimeras (PROTACs). By integrating mechanistic insights with structural and technological advancements, this work highlights emerging opportunities for the rational design of next-generation Mpro-targeted antivirals capable of addressing both current and future coronavirus threats.