Easy access to α-ketoamides as SARS-CoV-2 and MERS Mpro inhibitors via the PADAM oxidation route
Copyright © 2022 Elsevier Masson SAS. All rights reserved..
SARS-CoV-2 caused worldwide the current outbreak called COVID-19. Despite multiple countermeasures implemented, there is an urgent global need for new potent and efficient antiviral drugs against this pathogen. In this context, the main protease (Mpro) of SARS-CoV-2 is an essential viral enzyme and plays a pivotal role in viral replication and transcription. Its specific cleavage of polypeptides after a glutamine residue has been considered as a key element to design novel antiviral drugs. Herein, we reported the design, synthesis and structure-activity relationships of novel α-ketoamides as covalent reversible inhibitors of Mpro, exploiting the PADAM oxidation route. The reported compounds showed μM to nM activities in enzymatic and in the antiviral cell-based assays against SARS-CoV-2 Mpro. In order to assess inhibitors' binding mode, two co-crystal structures of SARS-CoV-2 Mpro in complex with our inhibitors were solved, which confirmed the covalent binding of the keto amide moiety to the catalytic Cys145 residue of Mpro. Finally, in order to interrogate potential broad-spectrum properties, we assessed a selection of compounds against MERS Mpro where they showed nM inhibitory potency, thus highlighting their potential as broad-spectrum coronavirus inhibitors.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:244 |
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| Enthalten in: |
European journal of medicinal chemistry - 244(2022) vom: 15. Dez., Seite 114853 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Pelliccia, Sveva [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 21.11.2022 Date Revised 17.12.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejmech.2022.114853 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM348464282 |
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| 500 | |a Date Revised 17.12.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 Elsevier Masson SAS. All rights reserved. | ||
| 520 | |a SARS-CoV-2 caused worldwide the current outbreak called COVID-19. Despite multiple countermeasures implemented, there is an urgent global need for new potent and efficient antiviral drugs against this pathogen. In this context, the main protease (Mpro) of SARS-CoV-2 is an essential viral enzyme and plays a pivotal role in viral replication and transcription. Its specific cleavage of polypeptides after a glutamine residue has been considered as a key element to design novel antiviral drugs. Herein, we reported the design, synthesis and structure-activity relationships of novel α-ketoamides as covalent reversible inhibitors of Mpro, exploiting the PADAM oxidation route. The reported compounds showed μM to nM activities in enzymatic and in the antiviral cell-based assays against SARS-CoV-2 Mpro. In order to assess inhibitors' binding mode, two co-crystal structures of SARS-CoV-2 Mpro in complex with our inhibitors were solved, which confirmed the covalent binding of the keto amide moiety to the catalytic Cys145 residue of Mpro. Finally, in order to interrogate potential broad-spectrum properties, we assessed a selection of compounds against MERS Mpro where they showed nM inhibitory potency, thus highlighting their potential as broad-spectrum coronavirus inhibitors | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Main protease inhibitors | |
| 650 | 4 | |a Multicomponent reactions | |
| 650 | 4 | |a PADAM-Oxidation | |
| 650 | 4 | |a SARS-CoV-2 | |
| 650 | 4 | |a α-ketoamides | |
| 650 | 7 | |a Coronavirus 3C Proteases |2 NLM | |
| 650 | 7 | |a EC 3.4.22.28 |2 NLM | |
| 650 | 7 | |a Protease Inhibitors |2 NLM | |
| 650 | 7 | |a Viral Nonstructural Proteins |2 NLM | |
| 650 | 7 | |a Cysteine Endopeptidases |2 NLM | |
| 650 | 7 | |a EC 3.4.22.- |2 NLM | |
| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 700 | 1 | |a Cerchia, Carmen |e verfasserin |4 aut | |
| 700 | 1 | |a Esposito, Francesca |e verfasserin |4 aut | |
| 700 | 1 | |a Cannalire, Rolando |e verfasserin |4 aut | |
| 700 | 1 | |a Corona, Angela |e verfasserin |4 aut | |
| 700 | 1 | |a Costanzi, Elisa |e verfasserin |4 aut | |
| 700 | 1 | |a Kuzikov, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Gribbon, Philip |e verfasserin |4 aut | |
| 700 | 1 | |a Zaliani, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Brindisi, Margherita |e verfasserin |4 aut | |
| 700 | 1 | |a Storici, Paola |e verfasserin |4 aut | |
| 700 | 1 | |a Tramontano, Enzo |e verfasserin |4 aut | |
| 700 | 1 | |a Summa, Vincenzo |e verfasserin |4 aut | |
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