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Opportunities and Challenges in Targeting the Proofreading Activity of SARS-CoV-2 Polymerase Complex

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic. While the development of vaccines and the emergence of antiviral therapeutics is promising, alternative strategies to combat COVID-19 (and potential future pandemics) remain an unmet need. Coronavirus...

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Autores principales: Deval, Jerome, Gurard-Levin, Zachary A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9103157/
https://www.ncbi.nlm.nih.gov/pubmed/35566268
http://dx.doi.org/10.3390/molecules27092918
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author Deval, Jerome
Gurard-Levin, Zachary A.
author_facet Deval, Jerome
Gurard-Levin, Zachary A.
author_sort Deval, Jerome
collection PubMed
description Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic. While the development of vaccines and the emergence of antiviral therapeutics is promising, alternative strategies to combat COVID-19 (and potential future pandemics) remain an unmet need. Coronaviruses feature a unique mechanism that may present opportunities for therapeutic intervention: the RNA polymerase complex of coronaviruses is distinct in its ability to proofread and remove mismatched nucleotides during genome replication and transcription. The proofreading activity has been linked to the exonuclease (ExoN) activity of non-structural protein 14 (NSP14). Here, we review the role of NSP14, and other NSPs, in SARS-CoV-2 replication and describe the assays that have been developed to assess the ExoN function. We also review the nucleoside analogs and non-nucleoside inhibitors known to interfere with the proofreading activity of NSP14. Although not yet validated, the potential use of non-nucleoside proofreading inhibitors in combination with chain-terminating nucleosides may be a promising avenue for the development of anti-CoV agents.
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spelling pubmed-91031572022-05-14 Opportunities and Challenges in Targeting the Proofreading Activity of SARS-CoV-2 Polymerase Complex Deval, Jerome Gurard-Levin, Zachary A. Molecules Review Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic. While the development of vaccines and the emergence of antiviral therapeutics is promising, alternative strategies to combat COVID-19 (and potential future pandemics) remain an unmet need. Coronaviruses feature a unique mechanism that may present opportunities for therapeutic intervention: the RNA polymerase complex of coronaviruses is distinct in its ability to proofread and remove mismatched nucleotides during genome replication and transcription. The proofreading activity has been linked to the exonuclease (ExoN) activity of non-structural protein 14 (NSP14). Here, we review the role of NSP14, and other NSPs, in SARS-CoV-2 replication and describe the assays that have been developed to assess the ExoN function. We also review the nucleoside analogs and non-nucleoside inhibitors known to interfere with the proofreading activity of NSP14. Although not yet validated, the potential use of non-nucleoside proofreading inhibitors in combination with chain-terminating nucleosides may be a promising avenue for the development of anti-CoV agents. MDPI 2022-05-03 /pmc/articles/PMC9103157/ /pubmed/35566268 http://dx.doi.org/10.3390/molecules27092918 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Deval, Jerome
Gurard-Levin, Zachary A.
Opportunities and Challenges in Targeting the Proofreading Activity of SARS-CoV-2 Polymerase Complex
title Opportunities and Challenges in Targeting the Proofreading Activity of SARS-CoV-2 Polymerase Complex
title_full Opportunities and Challenges in Targeting the Proofreading Activity of SARS-CoV-2 Polymerase Complex
title_fullStr Opportunities and Challenges in Targeting the Proofreading Activity of SARS-CoV-2 Polymerase Complex
title_full_unstemmed Opportunities and Challenges in Targeting the Proofreading Activity of SARS-CoV-2 Polymerase Complex
title_short Opportunities and Challenges in Targeting the Proofreading Activity of SARS-CoV-2 Polymerase Complex
title_sort opportunities and challenges in targeting the proofreading activity of sars-cov-2 polymerase complex
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9103157/
https://www.ncbi.nlm.nih.gov/pubmed/35566268
http://dx.doi.org/10.3390/molecules27092918
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