At the end of 2019, the new coronavirus caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suddenly raged, bringing a severe public health crisis to the world. No efficacious drugs are available so far. Therefore, it is urgent to design and develop anti-coronavirus clinical drugs. The 3CL protease is a promising key drug target, as it plays a pivotal role in viral replication and is highly conserved in all coronaviruses.
Recently, Luhua Lai’s group at the College of Chemistry and Molecular Engineering, Peking University, collaborated with Professor Wenjie Tan at the NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, China CDC, reported the inhibition potency of bardoxolone and bardoxolone methyl against SARS-CoV-2. They found that bardoxolone and bardoxolone methyl bind SARS-CoV-2 3CL protease in a reversible covalent manner. With full-time incubation, bardoxolone methyl and bardoxolone inhibit SARS-CoV-2 replication in Vero cells with EC50 values of 0.29 μM and 0.43 μM, respectively. Both compounds also inhibit the SARS-CoV-2 viral replication in human Calu-3 cells with EC50 values of 0.20 μM and 0.42 μM, respectively. Efficacies were also confirmed with visualization of virus nucleoprotein expression using immunofluorescence microscopy.
Bardoxolone and bardoxolone methyl are oleanolic acid derived semi-synthetic triterpenoids that activate the Nrf2 pathway and inhibit the NF-κB pathway. On April 26 2021, Reata Pharmaceuticals announced that the U.S. Food and Drug Administration accepted for filing the New Drug Application for bardoxolone methyl (bardoxolone) for the treatment of patients with chronic kidney disease caused by Alport syndrome. The steady-state plasma concentration of bardoxolone by intravenous infusion exceeds 1 μM at doses below the maximum tolerated doses, which is well above EC50 value against SARS-CoV-2. It was also reported that the Nrf2 pathway was suppressed in lung biopsies from COVID-19 patients. Thus, the Nrf2 activators bardoxolone and bardoxolone methyl can be developed as a multifaceted antiviral treatment strategy by inhibiting viral replication, promoting resolution of inflammation, providing robust cytoprotection, and facilitating tissue repair.
The related work was recently published in the Signal Transduction and Targeted Therapy (Sun Q, et al. “Bardoxolone and bardoxolone methyl, two Nrf2 activators in clinical trials, inhibit SARS-CoV-2 replication and its 3C-like protease”, DOI: 10.1038/s41392-021-00628-x). The first authors include Dr. Qi Sun, Dr. Fei Ye, Dr. Hao Liang, Dr. Hongbo Liu and the corresponding authors are Professor Luhua Lai and Professor Wenjie Tan. This research was funded in part by the Ministry of Science and Technology, the National Natural Science Foundation of China, the Fundamental Research Funds for the Central Universities, and the Beijing National Laboratory for Molecular Sciences.
Original link for the paper: https://www.nature.com/articles/s41392-021-00628-x
