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

He, Jun; Hu, Lijun; Huang, Xiaojun; Wang, Chenran; Zhang, Zhimin; Wang, Ying; Zhang, Dongmei; Ye, Wencai

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), similar to SARS-CoV and the Middle East respiratory syndrome coronavirus (MERS-CoV), which belong to the same β-coronavirus group, induces sever acute respiratory disease, threatening human health. Since the outbreak of SARS-CoV-2 infection began, the disease has rapidly spread worldwide. Thus, a search for effective drugs, able to inhibit the coronavirus, has become a global pursuit. The 3C-like protease (3CL(pro)), which hydrolyzes the polyprotein to produce functional proteins, is essential for coronavirus replication and considered an important therapeutic target for diseases caused by coronaviruses, including coronavirus disease 2019 (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 the recent developments in the structure of 3CL(pro) and its function in coronavirus replication and summarize new insights into 3CL(pro) inhibitors and their mechanisms of action. We also discuss the clinical application prospects and limitations of 3CL(pro) inhibitors for COVID-19 treatment.