Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Biophysics, COVID-19, Coronavirus, 3CLpro, Protease inhibitor, CATHEPSINS, Amides, Animals, Cathepsin L, Cell Line, Coronavirus 3C Proteases, Cricetinae, Cysteine Proteinase Inhibitors, Disease Models, Animal, Female, Humans, Inhibitory Concentration 50, Male, Mesocricetus, Reproducibility of Results, SARS-CoV-2, Serine Endopeptidases, Substrate Specificity, Virus Replication, COVID-19 Drug Treatment, 0304 Medicinal and Biomolecular Chemistry, 0601 Biochemistry and Cell Biology, 1101 Medical Biochemistry and Metabolomics, 3101 Biochemistry and cell biology, 3404 Medicinal and biomolecular chemistry

Abstract:

There is an urgent need for antivirals targeting the SARS-CoV-2 virus to fight the current COVID-19 pandemic. The SARS-CoV-2 main protease (3CLpro) represents a promising target for antiviral therapy. The lack of selectivity for some of the reported 3CLpro inhibitors, specifically versus cathepsin L, raises potential safety and efficacy concerns. ALG-097111 potently inhibited SARS-CoV-2 3CLpro (IC50 = 7 nM) without affecting the activity of human cathepsin L (IC50 > 10 μM). When ALG-097111 was dosed in hamsters challenged with SARS-CoV-2, a robust and significant 3.5 log10 (RNA copies/mg) reduction of the viral RNA copies and 3.7 log10 (TCID50/mg) reduction in the infectious virus titers in the lungs was observed. These results provide the first in vivo validation for the SARS-CoV-2 3CLpro as a promising therapeutic target for selective small molecule inhibitors.