Biochem Biophys Res Commun
. 2021 Mar 26;555:134-139.
doi: 10.1016/j.bbrc.2021.03.096. Online ahead of print.
ALG-097111, a potent and selective SARS-CoV-2 3-chymotrypsin-like cysteine protease inhibitor exhibits in vivo efficacy in a Syrian Hamster model
Koen Vandyck 1 , Rana Abdelnabi 2 , Kusum Gupta 3 , Dirk Jochmans 2 , Andreas Jekle 3 , Jerome Deval 3 , Dinah Misner 3 , Doroth?e Bardiot 4 , Caroline S Foo 2 , Cheng Liu 3 , Suping Ren 3 , Leonid Beigelman 5 , Lawrence M Blatt 5 , Sandro Boland 4 , Laura Vangeel 2 , Steven Dejonghe 2 , Patrick Chaltin 6 , Arnaud Marchand 4 , Vladimir Serebryany 3 , Antitsa Stoycheva 3 , Sushmita Chanda 3 , Julian A Symons 3 , Pierre Raboisson 7 , Johan Neyts 8
Affiliations
- PMID: 33813272
- DOI: 10.1016/j.bbrc.2021.03.096
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 ?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.
Keywords: 3CLpro; COVID-19; Coronavirus; Protease inhibitor.