Bardoxolone and bardoxolone methyl, two Nrf2 activators in clinical trials, inhibit SARS-CoV-2 replication and its 3C-like protease
Qi Sun, Fei Ye, Hao Liang, Hongbo Liu, Chunmei Li, Roujian Lu, Baoying Huang, Li Zhao, Wenjie Tan, Luhua Lai
Abstract
The outbreak of coronavirus disease 2019 (COVID-19) has become a severe threat to global public health. Although many drug repurposing researches have been carried out, no effective drugs have been found in clinical studies. 1 Among the viral proteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19, the 3C-like protease (3CL pro ), the main protease responsible for viral polyprotein processing, is highly conserved among coronaviruses and serves as a promising target for broad-spectrum anti-CoV therapy. A number of SARS-CoV 3CL pro inhibitors have been reported before. Recently, several SARS-CoV-2 3CL pro inhibitors were discovered by structural-based drug design and high-throughput screening. 2 Though these compounds showed encouraging antiviral activity in vitro, their in vivo efficacy, safety and metabolism need further investigation. There is a continuous and urgent need to discover new inhibitors with diverse chemical structures and novel mode of action. Many currently known coronavirus 3CL pro inhibitors act through covalent binding. 2 Covalent inhibitors are especially advantageous with enhanced therapeutic efficacy and minimized side effects, as exemplified by several approved anti-tumor covalent drugs. 3 Thus, the screening of covalent 3CL pro inhibitors, especially those with primary in vivo safety evaluation, may facilitate the discovery of antiviral agents.