ALG-097111, a potent and selective SARS-CoV-2 3-chymotrypsin-like cysteine protease inhibitor exhibits in vivo efficacy in a Syrian Hamster model

Vandyck, Koen; Abdelnabi, Rana; Gupta, Kusum; Jochmans, Dirk; Jekle, Andreas; Deval, Jerome; Misner, Dinah; Bardiot, Dorothée; Foo, Caroline S.; Liu, Cheng; Ren, Suping; Beigelman, Leonid; Blatt, Lawrence M.; Boland, Sandro; Vangeel, Laura; Dejonghe, Steven; Chaltin, Patrick; Marchand, Arnaud; Serebryany, Vladimir; Stoycheva, Antitsa; Chanda, Sushmita; Symons, Julian A.; Raboisson, Pierre; Neyts, Johan

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 (IC(50) = 7 nM) without affecting the activity of human cathepsin L (IC(50) > 10 μM). When ALG-097111 was dosed in hamsters challenged with SARS-CoV-2, a robust and significant 3.5 log(10) (RNA copies/mg) reduction of the viral RNA copies and 3.7 log(10) (TCID(50)/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.