Malleability of the SARS-CoV-2 3CL Mpro Active-Site Cavity Facilitates Binding of Clinical Antivirals
Published by Elsevier Ltd..
The COVID-19 pandemic caused by SARS-CoV-2 requires rapid development of specific therapeutics and vaccines. The main protease of SARS-CoV-2, 3CL Mpro, is an established drug target for the design of inhibitors to stop the virus replication. Repurposing existing clinical drugs can offer a faster route to treatments. Here, we report on the binding mode and inhibition properties of several inhibitors using room temperature X-ray crystallography and in vitro enzyme kinetics. The enzyme active-site cavity reveals a high degree of malleability, allowing aldehyde leupeptin and hepatitis C clinical protease inhibitors (telaprevir, narlaprevir, and boceprevir) to bind and inhibit SARS-CoV-2 3CL Mpro. Narlaprevir, boceprevir, and telaprevir are low-micromolar inhibitors, whereas the binding affinity of leupeptin is substantially weaker. Repurposing hepatitis C clinical drugs as COVID-19 treatments may be a useful option to pursue. The observed malleability of the enzyme active-site cavity should be considered for the successful design of specific protease inhibitors.
| Errataetall: |
CommentOn: Nat Commun. 2020 Jun 24;11(1):3202. - PMID 32581217 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:28 |
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| Enthalten in: |
Structure (London, England : 1993) - 28(2020), 12 vom: 01. Dez., Seite 1313-1320.e3 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kneller, Daniel W [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 09.12.2020 Date Revised 30.03.2024 published: Print-Electronic CommentOn: Nat Commun. 2020 Jun 24;11(1):3202. - PMID 32581217 Citation Status MEDLINE |
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| doi: |
10.1016/j.str.2020.10.007 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM317204009 |
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| 520 | |a The COVID-19 pandemic caused by SARS-CoV-2 requires rapid development of specific therapeutics and vaccines. The main protease of SARS-CoV-2, 3CL Mpro, is an established drug target for the design of inhibitors to stop the virus replication. Repurposing existing clinical drugs can offer a faster route to treatments. Here, we report on the binding mode and inhibition properties of several inhibitors using room temperature X-ray crystallography and in vitro enzyme kinetics. The enzyme active-site cavity reveals a high degree of malleability, allowing aldehyde leupeptin and hepatitis C clinical protease inhibitors (telaprevir, narlaprevir, and boceprevir) to bind and inhibit SARS-CoV-2 3CL Mpro. Narlaprevir, boceprevir, and telaprevir are low-micromolar inhibitors, whereas the binding affinity of leupeptin is substantially weaker. Repurposing hepatitis C clinical drugs as COVID-19 treatments may be a useful option to pursue. The observed malleability of the enzyme active-site cavity should be considered for the successful design of specific protease inhibitors | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
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| 650 | 4 | |a 3CL M(pro) | |
| 650 | 4 | |a 3CL main protease | |
| 650 | 4 | |a SARS-CoV-2 | |
| 650 | 4 | |a drug design | |
| 650 | 4 | |a enzyme kinetics | |
| 650 | 4 | |a hepatitis C clinical drugs | |
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| 650 | 4 | |a repurposing clinical drugs | |
| 650 | 4 | |a room temperature X-ray crystallography | |
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| 700 | 1 | |a O'Neill, Hugh M |e verfasserin |4 aut | |
| 700 | 1 | |a Coates, Leighton |e verfasserin |4 aut | |
| 700 | 1 | |a Kovalevsky, Andrey |e verfasserin |4 aut | |
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