tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Rana Abdelnabi[SUP] 2 [/SUP], Kusum Gupta[SUP] 3 [/SUP], Dirk Jochmans[SUP] 2 [/SUP], Andreas Jekle[SUP] 3 [/SUP], Jerome Deval[SUP] 3 [/SUP], Dinah Misner[SUP] 3 [/SUP], Doroth?e Bardiot[SUP] 4 [/SUP], Caroline S Foo[SUP] 2 [/SUP], Cheng Liu[SUP] 3 [/SUP], Suping Ren[SUP] 3 [/SUP], Leonid Beigelman[SUP] 5 [/SUP], Lawrence M Blatt[SUP] 5 [/SUP], Sandro Boland[SUP] 4 [/SUP], Laura Vangeel[SUP] 2 [/SUP], Steven Dejonghe[SUP] 2 [/SUP], Patrick Chaltin[SUP] 6 [/SUP], Arnaud Marchand[SUP] 4 [/SUP], Vladimir Serebryany[SUP] 3 [/SUP], Antitsa Stoycheva[SUP] 3 [/SUP], Sushmita Chanda[SUP] 3 [/SUP], Julian A Symons[SUP] 3 [/SUP], Pierre Raboisson[SUP] 7 [/SUP], Johan Neyts[SUP] 8 [/SUP]
Affiliations
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 (IC[SUB]50[/SUB] = 7 nM) without affecting the activity of human cathepsin L (IC[SUB]50[/SUB] > 10 ?M). When ALG-097111 was dosed in hamsters challenged with SARS-CoV-2, a robust and significant 3.5 log[SUB]10[/SUB] (RNA copies/mg) reduction of the viral RNA copies and 3.7 log[SUB]10[/SUB] (TCID[SUB]50[/SUB]/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.
. 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[SUP] 1 [/SUP], Rana Abdelnabi[SUP] 2 [/SUP], Kusum Gupta[SUP] 3 [/SUP], Dirk Jochmans[SUP] 2 [/SUP], Andreas Jekle[SUP] 3 [/SUP], Jerome Deval[SUP] 3 [/SUP], Dinah Misner[SUP] 3 [/SUP], Doroth?e Bardiot[SUP] 4 [/SUP], Caroline S Foo[SUP] 2 [/SUP], Cheng Liu[SUP] 3 [/SUP], Suping Ren[SUP] 3 [/SUP], Leonid Beigelman[SUP] 5 [/SUP], Lawrence M Blatt[SUP] 5 [/SUP], Sandro Boland[SUP] 4 [/SUP], Laura Vangeel[SUP] 2 [/SUP], Steven Dejonghe[SUP] 2 [/SUP], Patrick Chaltin[SUP] 6 [/SUP], Arnaud Marchand[SUP] 4 [/SUP], Vladimir Serebryany[SUP] 3 [/SUP], Antitsa Stoycheva[SUP] 3 [/SUP], Sushmita Chanda[SUP] 3 [/SUP], Julian A Symons[SUP] 3 [/SUP], Pierre Raboisson[SUP] 7 [/SUP], Johan Neyts[SUP] 8 [/SUP]
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 (IC[SUB]50[/SUB] = 7 nM) without affecting the activity of human cathepsin L (IC[SUB]50[/SUB] > 10 ?M). When ALG-097111 was dosed in hamsters challenged with SARS-CoV-2, a robust and significant 3.5 log[SUB]10[/SUB] (RNA copies/mg) reduction of the viral RNA copies and 3.7 log[SUB]10[/SUB] (TCID[SUB]50[/SUB]/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.