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
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+-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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
|---|---|
| Enthalten in: |
Emerging microbes & infections - 12(2023), 2 vom: 01. Dez., Seite 2246594 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Pérez-Vargas, Jimena [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 25.08.2023 Date Revised 16.02.2024 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.1080/22221751.2023.2246594 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM360549101 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM360549101 | ||
| 003 | DE-627 | ||
| 005 | 20240216232610.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1080/22221751.2023.2246594 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1295.xml |
| 035 | |a (DE-627)NLM360549101 | ||
| 035 | |a (NLM)37555275 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Pérez-Vargas, Jimena |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a 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 |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 25.08.2023 | ||
| 500 | |a Date Revised 16.02.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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+-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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a 3CLpro inhibitor | |
| 650 | 4 | |a SARS-CoV-2 3CLpro | |
| 650 | 4 | |a SARS-CoV-2 Omicron subvariants | |
| 650 | 4 | |a combination therapy | |
| 650 | 4 | |a computer-aided drug design | |
| 650 | 7 | |a Protease Inhibitors |2 NLM | |
| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 650 | 7 | |a (2S)-N-((2S)-1-(((2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-(methanesulfonamido)pentanediamide) |2 NLM | |
| 650 | 7 | |a nirmatrelvir and ritonavir drug combination |2 NLM | |
| 700 | 1 | |a Worrall, Liam J |e verfasserin |4 aut | |
| 700 | 1 | |a Olmstead, Andrea D |e verfasserin |4 aut | |
| 700 | 1 | |a Ton, Anh-Tien |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Jaeyong |e verfasserin |4 aut | |
| 700 | 1 | |a Villanueva, Ivan |e verfasserin |4 aut | |
| 700 | 1 | |a Thompson, Connor A H |e verfasserin |4 aut | |
| 700 | 1 | |a Dudek, Svenja |e verfasserin |4 aut | |
| 700 | 1 | |a Ennis, Siobhan |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Jason R |e verfasserin |4 aut | |
| 700 | 1 | |a Shapira, Tirosh |e verfasserin |4 aut | |
| 700 | 1 | |a De Guzman, Joshua |e verfasserin |4 aut | |
| 700 | 1 | |a Gang, Shutong |e verfasserin |4 aut | |
| 700 | 1 | |a Ban, Fuqiang |e verfasserin |4 aut | |
| 700 | 1 | |a Vuckovic, Marija |e verfasserin |4 aut | |
| 700 | 1 | |a Bielecki, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Kovacic, Suzana |e verfasserin |4 aut | |
| 700 | 1 | |a Kenward, Calem |e verfasserin |4 aut | |
| 700 | 1 | |a Hong, Christopher Yee |e verfasserin |4 aut | |
| 700 | 1 | |a Gordon, Danielle G |e verfasserin |4 aut | |
| 700 | 1 | |a Levett, Paul N |e verfasserin |4 aut | |
| 700 | 1 | |a Krajden, Mel |e verfasserin |4 aut | |
| 700 | 1 | |a Leduc, Richard |e verfasserin |4 aut | |
| 700 | 1 | |a Boudreault, Pierre-Luc |e verfasserin |4 aut | |
| 700 | 1 | |a Niikura, Masahiro |e verfasserin |4 aut | |
| 700 | 1 | |a Paetzel, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Young, Robert N |e verfasserin |4 aut | |
| 700 | 1 | |a Cherkasov, Artem |e verfasserin |4 aut | |
| 700 | 1 | |a Strynadka, Natalie C J |e verfasserin |4 aut | |
| 700 | 1 | |a Jean, François |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Emerging microbes & infections |d 2012 |g 12(2023), 2 vom: 01. Dez., Seite 2246594 |w (DE-627)NLM249608804 |x 2222-1751 |7 nnns |
| 773 | 1 | 8 | |g volume:12 |g year:2023 |g number:2 |g day:01 |g month:12 |g pages:2246594 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1080/22221751.2023.2246594 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 12 |j 2023 |e 2 |b 01 |c 12 |h 2246594 | ||