tetano
Editor, Senior Moderator
Emerg Microbes Infect
. 2023 Aug 9;2246594.
doi: 10.1080/22221751.2023.2246594. Online ahead of print. A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants
Jimena Pérez-Vargas[SUP] 1 [/SUP], Liam J Worrall[SUP] 2 [/SUP], Andrea D Olmstead[SUP] 1 [/SUP], Anh-Tien Ton[SUP] 3 [/SUP], Jaeyong Lee[SUP] 2 4 [/SUP], Ivan Villanueva[SUP] 1 [/SUP], Connor A H Thompson[SUP] 1 [/SUP], Svenja Dudek[SUP] 1 [/SUP], Siobhan Ennis[SUP] 5 [/SUP], Jason R Smith[SUP] 3 6 [/SUP], Tirosh Shapira[SUP] 1 [/SUP], Joshua De Guzman[SUP] 1 [/SUP], Shutong Gang[SUP] 1 [/SUP], Fuqiang Ban[SUP] 3 [/SUP], Marija Vuckovic[SUP] 2 [/SUP], Michael Bielecki[SUP] 6 [/SUP], Suzana Kovacic[SUP] 6 [/SUP], Calem Kenward[SUP] 2 [/SUP], Christopher Yee Hong[SUP] 1 [/SUP], Danielle G Gordon[SUP] 1 [/SUP], Paul N Levett[SUP] 7 8 [/SUP], Mel Krajden[SUP] 7 8 [/SUP], Richard Leduc[SUP] 9 [/SUP], Pierre-Luc Boudreault[SUP] 9 [/SUP], Masahiro Niikura[SUP] 5 [/SUP], Mark Paetzel[SUP] 4 [/SUP], Robert N Young[SUP] 6 [/SUP], Artem Cherkasov[SUP] 3 [/SUP], Natalie C J Strynadka[SUP] 2 [/SUP], François Jean[SUP] 1 [/SUP]
Affiliations
Antivirals with broad coronavirus activity are important for treating high-risk individuals exposed to the constantly evolving SARS-CoV-2 variants of concern (VOCs) as well as emerging drug-resistant variants. We developed and characterized a novel class of active-site-directed 3-chymotrypsin-like protease (3CLpro) inhibitors (C2-C5a). Our lead direct-acting antiviral (DAA), C5a, is a non-covalent, non-peptide with a dissociation constant of 170 nM against recombinant SARS-CoV-2 3CLpro. The compounds C2-C5a exhibit broad-spectrum activity against Omicron subvariants (BA.5, BQ.1.1, and XBB.1.5) and seasonal human coronavirus-229E infection in human cells. Notably, C5a has median effective concentrations of 30 - 50 nM against BQ.1.1 and XBB.1.5 in two different human cell lines. X-ray crystallography has confirmed the unique binding modes of C2-C5a to the 3CLpro, which can limit virus cross-resistance to emerging Paxlovid-resistant variants. We tested the effect of C5a with two of our newly discovered host-directed antivirals (HDAs): N-0385, a TMPRSS2 inhibitor, and bafilomycin D (BafD), a human vacuolar H[SUP]+[/SUP]-ATPase [V-ATPase] inhibitor. We demonstrated a synergistic action of C5a in combination with N-0385 and BafD against Omicron BA.5 infection in human Calu-3 lung cells. Our findings underscore that a SARS-CoV-2 multi-targeted treatment for circulating Omicron subvariants based on DAAs (C5a) and HDAs (N-0385 or BafD) can lead to therapeutic benefits by enhancing treatment efficacy. Furthermore, the high-resolution structures of SARS-CoV-2 3CLpro in complex with C2-C5a will facilitate future rational optimization of our novel broad-spectrum active-site-directed 3C-like protease inhibitors.
Keywords: 3CLpro inhibitor; SARS-CoV-2 3CLpro; SARS-CoV-2 Omicron subvariants; combination therapy; computer-aided drug design.
. 2023 Aug 9;2246594.
doi: 10.1080/22221751.2023.2246594. Online ahead of print. A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants
Jimena Pérez-Vargas[SUP] 1 [/SUP], Liam J Worrall[SUP] 2 [/SUP], Andrea D Olmstead[SUP] 1 [/SUP], Anh-Tien Ton[SUP] 3 [/SUP], Jaeyong Lee[SUP] 2 4 [/SUP], Ivan Villanueva[SUP] 1 [/SUP], Connor A H Thompson[SUP] 1 [/SUP], Svenja Dudek[SUP] 1 [/SUP], Siobhan Ennis[SUP] 5 [/SUP], Jason R Smith[SUP] 3 6 [/SUP], Tirosh Shapira[SUP] 1 [/SUP], Joshua De Guzman[SUP] 1 [/SUP], Shutong Gang[SUP] 1 [/SUP], Fuqiang Ban[SUP] 3 [/SUP], Marija Vuckovic[SUP] 2 [/SUP], Michael Bielecki[SUP] 6 [/SUP], Suzana Kovacic[SUP] 6 [/SUP], Calem Kenward[SUP] 2 [/SUP], Christopher Yee Hong[SUP] 1 [/SUP], Danielle G Gordon[SUP] 1 [/SUP], Paul N Levett[SUP] 7 8 [/SUP], Mel Krajden[SUP] 7 8 [/SUP], Richard Leduc[SUP] 9 [/SUP], Pierre-Luc Boudreault[SUP] 9 [/SUP], Masahiro Niikura[SUP] 5 [/SUP], Mark Paetzel[SUP] 4 [/SUP], Robert N Young[SUP] 6 [/SUP], Artem Cherkasov[SUP] 3 [/SUP], Natalie C J Strynadka[SUP] 2 [/SUP], François Jean[SUP] 1 [/SUP]
Affiliations
- PMID: 37555275
- DOI: 10.1080/22221751.2023.2246594
Antivirals with broad coronavirus activity are important for treating high-risk individuals exposed to the constantly evolving SARS-CoV-2 variants of concern (VOCs) as well as emerging drug-resistant variants. We developed and characterized a novel class of active-site-directed 3-chymotrypsin-like protease (3CLpro) inhibitors (C2-C5a). Our lead direct-acting antiviral (DAA), C5a, is a non-covalent, non-peptide with a dissociation constant of 170 nM against recombinant SARS-CoV-2 3CLpro. The compounds C2-C5a exhibit broad-spectrum activity against Omicron subvariants (BA.5, BQ.1.1, and XBB.1.5) and seasonal human coronavirus-229E infection in human cells. Notably, C5a has median effective concentrations of 30 - 50 nM against BQ.1.1 and XBB.1.5 in two different human cell lines. X-ray crystallography has confirmed the unique binding modes of C2-C5a to the 3CLpro, which can limit virus cross-resistance to emerging Paxlovid-resistant variants. We tested the effect of C5a with two of our newly discovered host-directed antivirals (HDAs): N-0385, a TMPRSS2 inhibitor, and bafilomycin D (BafD), a human vacuolar H[SUP]+[/SUP]-ATPase [V-ATPase] inhibitor. We demonstrated a synergistic action of C5a in combination with N-0385 and BafD against Omicron BA.5 infection in human Calu-3 lung cells. Our findings underscore that a SARS-CoV-2 multi-targeted treatment for circulating Omicron subvariants based on DAAs (C5a) and HDAs (N-0385 or BafD) can lead to therapeutic benefits by enhancing treatment efficacy. Furthermore, the high-resolution structures of SARS-CoV-2 3CLpro in complex with C2-C5a will facilitate future rational optimization of our novel broad-spectrum active-site-directed 3C-like protease inhibitors.
Keywords: 3CLpro inhibitor; SARS-CoV-2 3CLpro; SARS-CoV-2 Omicron subvariants; combination therapy; computer-aided drug design.