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, K.; Abdelnabi, R.; Gupta, K.; Jochmans, D.; Jekle, A.; Deval, J.; Misner, D.; Bardiot, D.; Foo, C. S.; Liu, C.; Ren, S.; Beigelman, L.; Blatt, L. M.; Boland, S.; Vangeel, L.; Dejonghe, S.; Chaltin, P.; Marchand, A.; Serebryany, V.; Stoycheva, A.; Chanda, S.; Symons, J. A.; Raboisson, P.; Neyts, J.

doi:10.1101/2021.02.14.431129

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bioRxiv · 10.1101/2021.02.14.431129

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

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Abstract

O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY 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 M). 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.

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Vandyck, K., Abdelnabi, R., Gupta, K., Jochmans, D., Jekle, A., Deval, J., Misner, D., Bardiot, D., Foo, C. S., Liu, C., Ren, S., Beigelman, L., Blatt, L. M., Boland, S., Vangeel, L., Dejonghe, S., Chaltin, P., Marchand, A., Serebryany, V., Stoycheva, A., Chanda, S., Symons, J. A., Raboisson, P., Neyts, J.. 2021-02-15. ALG-097111, a potent and selective SARS-CoV-2 3-chymotrypsin-like cysteine protease inhibitor exhibits in vivo efficacy in a Syrian Hamster model. https://doi.org/10.1101/2021.02.14.431129

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