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Rational design of highly potent broad-spectrum enterovirus inhibitors targeting the nonstructural protein 2C

There is a great need for antiviral drugs to treat enterovirus (EV) and rhinovirus (RV) infections, which can be severe and occasionally life-threatening. The conserved nonstructural protein 2C, which is an AAA+ ATPase, is a promising target for drug development. Here, we present a structure-activit...

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Autores principales: Bauer, Lisa, Manganaro, Roberto, Zonsics, Birgit, Hurdiss, Daniel L., Zwaagstra, Marleen, Donselaar, Tim, Welter, Naemi G. E., van Kleef, Regina G. D. M., Lopez, Moira Lorenzo, Bevilacqua, Federica, Raman, Thamidur, Ferla, Salvatore, Bassetto, Marcella, Neyts, Johan, Strating, Jeroen R. P. M., Westerink, Remco H. S., Brancale, Andrea, van Kuppeveld, Frank J. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673538/
https://www.ncbi.nlm.nih.gov/pubmed/33156822
http://dx.doi.org/10.1371/journal.pbio.3000904
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author Bauer, Lisa
Manganaro, Roberto
Zonsics, Birgit
Hurdiss, Daniel L.
Zwaagstra, Marleen
Donselaar, Tim
Welter, Naemi G. E.
van Kleef, Regina G. D. M.
Lopez, Moira Lorenzo
Bevilacqua, Federica
Raman, Thamidur
Ferla, Salvatore
Bassetto, Marcella
Neyts, Johan
Strating, Jeroen R. P. M.
Westerink, Remco H. S.
Brancale, Andrea
van Kuppeveld, Frank J. M.
author_facet Bauer, Lisa
Manganaro, Roberto
Zonsics, Birgit
Hurdiss, Daniel L.
Zwaagstra, Marleen
Donselaar, Tim
Welter, Naemi G. E.
van Kleef, Regina G. D. M.
Lopez, Moira Lorenzo
Bevilacqua, Federica
Raman, Thamidur
Ferla, Salvatore
Bassetto, Marcella
Neyts, Johan
Strating, Jeroen R. P. M.
Westerink, Remco H. S.
Brancale, Andrea
van Kuppeveld, Frank J. M.
author_sort Bauer, Lisa
collection PubMed
description There is a great need for antiviral drugs to treat enterovirus (EV) and rhinovirus (RV) infections, which can be severe and occasionally life-threatening. The conserved nonstructural protein 2C, which is an AAA+ ATPase, is a promising target for drug development. Here, we present a structure-activity relationship study of a previously identified compound that targets the 2C protein of EV-A71 and several EV-B species members, but not poliovirus (PV) (EV-C species). This compound is structurally related to the Food and Drug Administration (FDA)-approved drug fluoxetine—which also targets 2C—but has favorable chemical properties. We identified several compounds with increased antiviral potency and broadened activity. Four compounds showed broad-spectrum EV and RV activity and inhibited contemporary strains of emerging EVs of public health concern, including EV-A71, coxsackievirus (CV)-A24v, and EV-D68. Importantly, unlike (S)-fluoxetine, these compounds are no longer neuroactive. By raising resistant EV-A71, CV-B3, and EV-D68 variants against one of these inhibitors, we identified novel 2C resistance mutations. Reverse engineering of these mutations revealed a conserved mechanism of resistance development. Resistant viruses first acquired a mutation in, or adjacent to, the α2 helix of 2C. This mutation disrupted compound binding and provided drug resistance, but this was at the cost of viral fitness. Additional mutations at distantly localized 2C residues were then acquired to increase resistance and/or to compensate for the loss of fitness. Using computational methods to identify solvent accessible tunnels near the α2 helix in the EV-A71 and PV 2C crystal structures, a conserved binding pocket of the inhibitors is proposed.
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spelling pubmed-76735382020-11-19 Rational design of highly potent broad-spectrum enterovirus inhibitors targeting the nonstructural protein 2C Bauer, Lisa Manganaro, Roberto Zonsics, Birgit Hurdiss, Daniel L. Zwaagstra, Marleen Donselaar, Tim Welter, Naemi G. E. van Kleef, Regina G. D. M. Lopez, Moira Lorenzo Bevilacqua, Federica Raman, Thamidur Ferla, Salvatore Bassetto, Marcella Neyts, Johan Strating, Jeroen R. P. M. Westerink, Remco H. S. Brancale, Andrea van Kuppeveld, Frank J. M. PLoS Biol Research Article There is a great need for antiviral drugs to treat enterovirus (EV) and rhinovirus (RV) infections, which can be severe and occasionally life-threatening. The conserved nonstructural protein 2C, which is an AAA+ ATPase, is a promising target for drug development. Here, we present a structure-activity relationship study of a previously identified compound that targets the 2C protein of EV-A71 and several EV-B species members, but not poliovirus (PV) (EV-C species). This compound is structurally related to the Food and Drug Administration (FDA)-approved drug fluoxetine—which also targets 2C—but has favorable chemical properties. We identified several compounds with increased antiviral potency and broadened activity. Four compounds showed broad-spectrum EV and RV activity and inhibited contemporary strains of emerging EVs of public health concern, including EV-A71, coxsackievirus (CV)-A24v, and EV-D68. Importantly, unlike (S)-fluoxetine, these compounds are no longer neuroactive. By raising resistant EV-A71, CV-B3, and EV-D68 variants against one of these inhibitors, we identified novel 2C resistance mutations. Reverse engineering of these mutations revealed a conserved mechanism of resistance development. Resistant viruses first acquired a mutation in, or adjacent to, the α2 helix of 2C. This mutation disrupted compound binding and provided drug resistance, but this was at the cost of viral fitness. Additional mutations at distantly localized 2C residues were then acquired to increase resistance and/or to compensate for the loss of fitness. Using computational methods to identify solvent accessible tunnels near the α2 helix in the EV-A71 and PV 2C crystal structures, a conserved binding pocket of the inhibitors is proposed. Public Library of Science 2020-11-06 /pmc/articles/PMC7673538/ /pubmed/33156822 http://dx.doi.org/10.1371/journal.pbio.3000904 Text en © 2020 Bauer et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Bauer, Lisa
Manganaro, Roberto
Zonsics, Birgit
Hurdiss, Daniel L.
Zwaagstra, Marleen
Donselaar, Tim
Welter, Naemi G. E.
van Kleef, Regina G. D. M.
Lopez, Moira Lorenzo
Bevilacqua, Federica
Raman, Thamidur
Ferla, Salvatore
Bassetto, Marcella
Neyts, Johan
Strating, Jeroen R. P. M.
Westerink, Remco H. S.
Brancale, Andrea
van Kuppeveld, Frank J. M.
Rational design of highly potent broad-spectrum enterovirus inhibitors targeting the nonstructural protein 2C
title Rational design of highly potent broad-spectrum enterovirus inhibitors targeting the nonstructural protein 2C
title_full Rational design of highly potent broad-spectrum enterovirus inhibitors targeting the nonstructural protein 2C
title_fullStr Rational design of highly potent broad-spectrum enterovirus inhibitors targeting the nonstructural protein 2C
title_full_unstemmed Rational design of highly potent broad-spectrum enterovirus inhibitors targeting the nonstructural protein 2C
title_short Rational design of highly potent broad-spectrum enterovirus inhibitors targeting the nonstructural protein 2C
title_sort rational design of highly potent broad-spectrum enterovirus inhibitors targeting the nonstructural protein 2c
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673538/
https://www.ncbi.nlm.nih.gov/pubmed/33156822
http://dx.doi.org/10.1371/journal.pbio.3000904
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