Potential of coronavirus 3C-like protease inhibitors for the development of new anti-SARS-CoV-2 drugs: Insights from structures of protease and inhibitors

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), similar to SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), which belong to the same Betacoronavirus genus, induces severe acute respiratory disease that is a threat to human health. Since the outbreak of infection by SARS-CoV-2 began, which causes coronavirus disease 2019 (COVID-19), the disease has rapidly spread worldwide. Thus, a search for effective drugs able to inhibit SARS-CoV-2 has become a global pursuit. The 3C-like protease (3CL(pro)), which hydrolyses viral polyproteins to produce functional proteins, is essential for coronavirus replication and is considered an important therapeutic target for diseases caused by coronaviruses, including COVID-19. Many 3CL(pro) inhibitors have been proposed and some new drug candidates have achieved success in preclinical studies. In this review, we briefly describe recent developments in determining the structure of 3CL(pro) and its function in coronavirus replication and summarise new insights into 3CL(pro) inhibitors and their mechanisms of action. The clinical application prospects and limitations of 3CL(pro) inhibitors for COVID-19 treatment are also discussed.