tetano
Editor, Senior Moderator
Arch Pharm (Weinheim)
. 2022 Oct 31;e2200371.
doi: 10.1002/ardp.202200371. Online ahead of print.
BC-11 is a covalent TMPRSS2 fragment inhibitor that impedes SARS-CoV-2 host cell entry
Aurélien F A Moumbock[SUP] 1 [/SUP], Hoai T T Tran[SUP] 2 [/SUP], Evelyn Lamy[SUP] 2 [/SUP], Stefan Günther[SUP] 1 [/SUP]
Affiliations
Abstract
Host cell entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is facilitated via priming of its spike glycoprotein by the human transmembrane protease serine 2 (TMPRSS2). Although camostat and nafamostat are two highly potent covalent TMPRSS2 inhibitors, they nevertheless did not hold promise in COVID-19 clinical trials, presumably due to their short plasma half-lives. Herein, we report an integrative chemogenomics approach based on computational modeling and in vitro enzymatic assays, for repurposing serine-targeted covalent inhibitors. This led to the identification of BC-11 as a covalent TMPRSS2 inhibitor displaying a unique selectivity profile for serine proteases, ascribable to its boronic acid warhead. BC-11 showed modest inhibition of SARS-CoV-2 (omicron variant) spike pseudotyped particles in a cell-based entry assay, and a combination of BC-11 and AHN 1-055 (a spike glycoprotein inhibitor) demonstrated better viral entry inhibition than either compound alone. Given its low molecular weight and good activity against TMPRSS2, BC-11 qualifies as a good starting point for further structural optimizations.
Keywords: BC-11; CovPDB; SARS-CoV-2 cell entry; TMPRSS2; targeted covalent inhibitor.
. 2022 Oct 31;e2200371.
doi: 10.1002/ardp.202200371. Online ahead of print.
BC-11 is a covalent TMPRSS2 fragment inhibitor that impedes SARS-CoV-2 host cell entry
Aurélien F A Moumbock[SUP] 1 [/SUP], Hoai T T Tran[SUP] 2 [/SUP], Evelyn Lamy[SUP] 2 [/SUP], Stefan Günther[SUP] 1 [/SUP]
Affiliations
- PMID: 36316225
- DOI: 10.1002/ardp.202200371
Abstract
Host cell entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is facilitated via priming of its spike glycoprotein by the human transmembrane protease serine 2 (TMPRSS2). Although camostat and nafamostat are two highly potent covalent TMPRSS2 inhibitors, they nevertheless did not hold promise in COVID-19 clinical trials, presumably due to their short plasma half-lives. Herein, we report an integrative chemogenomics approach based on computational modeling and in vitro enzymatic assays, for repurposing serine-targeted covalent inhibitors. This led to the identification of BC-11 as a covalent TMPRSS2 inhibitor displaying a unique selectivity profile for serine proteases, ascribable to its boronic acid warhead. BC-11 showed modest inhibition of SARS-CoV-2 (omicron variant) spike pseudotyped particles in a cell-based entry assay, and a combination of BC-11 and AHN 1-055 (a spike glycoprotein inhibitor) demonstrated better viral entry inhibition than either compound alone. Given its low molecular weight and good activity against TMPRSS2, BC-11 qualifies as a good starting point for further structural optimizations.
Keywords: BC-11; CovPDB; SARS-CoV-2 cell entry; TMPRSS2; targeted covalent inhibitor.