Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection
Protease inhibitors targeting viral 3C-like protease are attractive therapeutic options for COVID-19. Here, we synthesized deuterated variants of a coronavirus protease inhibitor, GC376, and determined the therapeutic efficacy in a lethal mouse model. The transgenic mice infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a causative agent of COVID-19, develop lung pathology resembling that of severe COVID-19 patients and were used for antiviral drug testing. The deuterated variants of GC376 have improved potency against SARS-CoV-2 in in vitro assays. Furthermore, treatment with a deuterated variant starting at 24 h postinfection resulted in significantly increased survival of mice compared to vehicle-treated mice. The results suggest that deuterated variants have excellent potential as antiviral agents against SARS-CoV-2. Coordinates and structure factors for the 3CLpro inhibitor complexes are deposited in the Worldwide Protein Data Bank with the following accession codes: SARS-CoV 3CLpro with inhibitor 2 ([7K0G][1]), and 5 ([7K0H][2]); SARS-CoV-2 3CLpro with inhibitor 2 ([7K0E][3]), and 5 ([7K0F][4]). [1]: http://www.rcsb.org/pdb/explore/explore.do?structureId=7K0G [2]: http://www.rcsb.org/pdb/explore/explore.do?structureId=7K0H [3]: http://www.rcsb.org/pdb/explore/explore.do?structureId=7K0E [4]: http://www.rcsb.org/pdb/explore/explore.do?structureId=7K0F
