1. ALG-097111, a potent and selective SARS-CoV-2 3-chymotrypsin-like cysteine protease inhibitor exhibits in vivo efficacy in a Syrian Hamster model
- Author
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Leonid Beigelman, Jerome Deval, Lawrence M. Blatt, Dorothée Bardiot, Laura Vangeel, Sandro Boland, Johan Neyts, Cheng Liu, Steven Dejonghe, Dinah Misner, Andreas Jekle, Pierre Raboisson, Sushmita Mukherjee Chanda, Vladimir Serebryany, Caroline S. Foo, Koen Vandyck, Arnaud Marchand, Suping Ren, Julian A. Symons, Patrick Chaltin, Kusum Gupta, Antitsa Dimitrova Stoycheva, Dirk Jochmans, and Rana Abdelnabi
- Subjects
0301 basic medicine ,Male ,Antagonists & inhibitors ,medicine.medical_treatment ,Cathepsin L ,viruses ,Biophysics ,Pharmacology ,Cysteine Proteinase Inhibitors ,Virus Replication ,Biochemistry ,Virus ,Article ,Cell Line ,Substrate Specificity ,03 medical and health sciences ,Inhibitory Concentration 50 ,0302 clinical medicine ,Cricetinae ,medicine ,Animals ,Humans ,Protease inhibitor (pharmacology) ,Molecular Biology ,Coronavirus 3C Proteases ,Protease ,biology ,Mesocricetus ,Chemistry ,SARS-CoV-2 ,Serine Endopeptidases ,Reproducibility of Results ,3CLpro ,COVID-19 ,Cell Biology ,biology.organism_classification ,Cysteine protease ,Amides ,COVID-19 Drug Treatment ,Coronavirus ,Disease Models, Animal ,030104 developmental biology ,Protease inhibitor ,030220 oncology & carcinogenesis ,biology.protein ,Female - 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., Graphical abstract Image 1
- Published
- 2021