Targeting SARS-CoV-2 nonstructural protein 3: Function, structure, inhibition, and perspective in drug discovery

•Nsp3 of SARS-CoV-2, including PLpro and Mac1, is essential for replication of the virus.•Function, structure and mechanism of catalysis of PLpro and Mac1 are reviewed.•Small-molecule inhibitors of PLpro and Mac1 are summarized.•Protein-inhibitor interactions of representative compounds are described. As a highly contagious human pathogen, severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) has infected billions of people worldwide with more than 6 million deaths. With several effective vaccines and antiviral drugs now available, the SARS-CoV-2 pandemic been brought under control. However, a new pathogenic coronavirus could emerge in the future, given the zoonotic nature of this virus. Natural evolution and drug-induced mutations of SARS-CoV-2 also require continued efforts for new anti-coronavirus drugs. Nonstructural protein (nsp) 3 of CoVs is a large, multifunctional protein, containing a papain-like protease (PLpro) and a macrodomain (Mac1), which are essential for viral replication. Here, we provide a comprehensive review of the function, structure, and inhibition of SARS-CoV/-CoV-2 PLpro and Mac1. We also discuss advances in, and challenges to, the discovery of drugs against these targets.