Alkyne Derivatives of SARS-CoV-2 Main Protease Inhibitors Including Nirmatrelvir Inhibit by Reacting Covalently with the Nucleophilic Cysteine
Nirmatrelvir (PF-07321332) is a nitrile-bearing small-molecule inhibitor that, in combination with ritonavir, is used to treat infections by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Nirmatrelvir interrupts the viral life cycle by inhibiting the SARS-CoV-2 main protease (Mpro), which is essential for processing viral polyproteins into functional nonstructural proteins. We report studies which reveal that derivatives of nirmatrelvir and other Mpro inhibitors with a nonactivated terminal alkyne group positioned similarly to the electrophilic nitrile of nirmatrelvir can efficiently inhibit isolated Mpro and SARS-CoV-2 replication in cells. Mass spectrometric and crystallographic evidence shows that the alkyne derivatives inhibit Mpro by apparent irreversible covalent reactions with the active site cysteine (Cys145), while the analogous nitriles react reversibly. The results highlight the potential for irreversible covalent inhibition of Mpro and other nucleophilic cysteine proteases by alkynes, which, in contrast to nitriles, can be functionalized at their terminal position to optimize inhibition and selectivity, as well as pharmacodynamic and pharmacokinetic properties.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:66 |
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| Enthalten in: |
Journal of medicinal chemistry - 66(2023), 4 vom: 23. Feb., Seite 2663-2680 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Brewitz, Lennart [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 20.03.2023 Date Revised 31.08.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.2c01627 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM352677627 |
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| 100 | 1 | |a Brewitz, Lennart |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Alkyne Derivatives of SARS-CoV-2 Main Protease Inhibitors Including Nirmatrelvir Inhibit by Reacting Covalently with the Nucleophilic Cysteine |
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| 500 | |a Date Revised 31.08.2023 | ||
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Nirmatrelvir (PF-07321332) is a nitrile-bearing small-molecule inhibitor that, in combination with ritonavir, is used to treat infections by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Nirmatrelvir interrupts the viral life cycle by inhibiting the SARS-CoV-2 main protease (Mpro), which is essential for processing viral polyproteins into functional nonstructural proteins. We report studies which reveal that derivatives of nirmatrelvir and other Mpro inhibitors with a nonactivated terminal alkyne group positioned similarly to the electrophilic nitrile of nirmatrelvir can efficiently inhibit isolated Mpro and SARS-CoV-2 replication in cells. Mass spectrometric and crystallographic evidence shows that the alkyne derivatives inhibit Mpro by apparent irreversible covalent reactions with the active site cysteine (Cys145), while the analogous nitriles react reversibly. The results highlight the potential for irreversible covalent inhibition of Mpro and other nucleophilic cysteine proteases by alkynes, which, in contrast to nitriles, can be functionalized at their terminal position to optimize inhibition and selectivity, as well as pharmacodynamic and pharmacokinetic properties | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Dumjahn, Leo |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Yilin |e verfasserin |4 aut | |
| 700 | 1 | |a Owen, C David |e verfasserin |4 aut | |
| 700 | 1 | |a Laidlaw, Stephen M |e verfasserin |4 aut | |
| 700 | 1 | |a Malla, Tika R |e verfasserin |4 aut | |
| 700 | 1 | |a Nguyen, Dung |e verfasserin |4 aut | |
| 700 | 1 | |a Lukacik, Petra |e verfasserin |4 aut | |
| 700 | 1 | |a Salah, Eidarus |e verfasserin |4 aut | |
| 700 | 1 | |a Crawshaw, Adam D |e verfasserin |4 aut | |
| 700 | 1 | |a Warren, Anna J |e verfasserin |4 aut | |
| 700 | 1 | |a Trincao, Jose |e verfasserin |4 aut | |
| 700 | 1 | |a Strain-Damerell, Claire |e verfasserin |4 aut | |
| 700 | 1 | |a Carroll, Miles W |e verfasserin |4 aut | |
| 700 | 1 | |a Walsh, Martin A |e verfasserin |4 aut | |
| 700 | 1 | |a Schofield, Christopher J |e verfasserin |4 aut | |
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