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Structural Investigations on Novel Non-Nucleoside Inhibitors of Human Norovirus Polymerase
Human norovirus is the first cause of foodborne disease worldwide, leading to extensive outbreaks of acute gastroenteritis, and causing around 200,000 children to die annually in developing countries. No specific vaccines or antiviral agents are currently available, with therapeutic options limited...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9864251/ https://www.ncbi.nlm.nih.gov/pubmed/36680114 http://dx.doi.org/10.3390/v15010074 |
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author | Giancotti, Gilda Nannetti, Giulio Padalino, Gilda Landini, Martina Santos-Ferreira, Nanci Van Dycke, Jana Naccarato, Valentina Patel, Usheer Silvestri, Romano Neyts, Johan Gozalbo-Rovira, Roberto Rodríguez-Díaz, Jésus Rocha-Pereira, Joana Brancale, Andrea Ferla, Salvatore Bassetto, Marcella |
author_facet | Giancotti, Gilda Nannetti, Giulio Padalino, Gilda Landini, Martina Santos-Ferreira, Nanci Van Dycke, Jana Naccarato, Valentina Patel, Usheer Silvestri, Romano Neyts, Johan Gozalbo-Rovira, Roberto Rodríguez-Díaz, Jésus Rocha-Pereira, Joana Brancale, Andrea Ferla, Salvatore Bassetto, Marcella |
author_sort | Giancotti, Gilda |
collection | PubMed |
description | Human norovirus is the first cause of foodborne disease worldwide, leading to extensive outbreaks of acute gastroenteritis, and causing around 200,000 children to die annually in developing countries. No specific vaccines or antiviral agents are currently available, with therapeutic options limited to supportive care to prevent dehydration. The infection can become severe and lead to life-threatening complications in young children, the elderly and immunocompromised individuals, leading to a clear need for antiviral agents, to be used as treatments and as prophylactic measures in case of outbreaks. Due to the key role played by the viral RNA-dependent RNA polymerase (RdRp) in the virus life cycle, this enzyme is a promising target for antiviral drug discovery. In previous studies, following in silico investigations, we identified different small-molecule inhibitors of this enzyme. In this study, we rationally modified five identified scaffolds, to further explore structure–activity relationships, and to enhance binding to the RdRp. The newly designed compounds were synthesized according to multiple-step synthetic routes and evaluated for their inhibition of the enzyme in vitro. New inhibitors with low micromolar inhibitory activity of the RdRp were identified, which provide a promising basis for further hit-to-lead optimization. |
format | Online Article Text |
id | pubmed-9864251 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-98642512023-01-22 Structural Investigations on Novel Non-Nucleoside Inhibitors of Human Norovirus Polymerase Giancotti, Gilda Nannetti, Giulio Padalino, Gilda Landini, Martina Santos-Ferreira, Nanci Van Dycke, Jana Naccarato, Valentina Patel, Usheer Silvestri, Romano Neyts, Johan Gozalbo-Rovira, Roberto Rodríguez-Díaz, Jésus Rocha-Pereira, Joana Brancale, Andrea Ferla, Salvatore Bassetto, Marcella Viruses Article Human norovirus is the first cause of foodborne disease worldwide, leading to extensive outbreaks of acute gastroenteritis, and causing around 200,000 children to die annually in developing countries. No specific vaccines or antiviral agents are currently available, with therapeutic options limited to supportive care to prevent dehydration. The infection can become severe and lead to life-threatening complications in young children, the elderly and immunocompromised individuals, leading to a clear need for antiviral agents, to be used as treatments and as prophylactic measures in case of outbreaks. Due to the key role played by the viral RNA-dependent RNA polymerase (RdRp) in the virus life cycle, this enzyme is a promising target for antiviral drug discovery. In previous studies, following in silico investigations, we identified different small-molecule inhibitors of this enzyme. In this study, we rationally modified five identified scaffolds, to further explore structure–activity relationships, and to enhance binding to the RdRp. The newly designed compounds were synthesized according to multiple-step synthetic routes and evaluated for their inhibition of the enzyme in vitro. New inhibitors with low micromolar inhibitory activity of the RdRp were identified, which provide a promising basis for further hit-to-lead optimization. MDPI 2022-12-27 /pmc/articles/PMC9864251/ /pubmed/36680114 http://dx.doi.org/10.3390/v15010074 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 | Article Giancotti, Gilda Nannetti, Giulio Padalino, Gilda Landini, Martina Santos-Ferreira, Nanci Van Dycke, Jana Naccarato, Valentina Patel, Usheer Silvestri, Romano Neyts, Johan Gozalbo-Rovira, Roberto Rodríguez-Díaz, Jésus Rocha-Pereira, Joana Brancale, Andrea Ferla, Salvatore Bassetto, Marcella Structural Investigations on Novel Non-Nucleoside Inhibitors of Human Norovirus Polymerase |
title | Structural Investigations on Novel Non-Nucleoside Inhibitors of Human Norovirus Polymerase |
title_full | Structural Investigations on Novel Non-Nucleoside Inhibitors of Human Norovirus Polymerase |
title_fullStr | Structural Investigations on Novel Non-Nucleoside Inhibitors of Human Norovirus Polymerase |
title_full_unstemmed | Structural Investigations on Novel Non-Nucleoside Inhibitors of Human Norovirus Polymerase |
title_short | Structural Investigations on Novel Non-Nucleoside Inhibitors of Human Norovirus Polymerase |
title_sort | structural investigations on novel non-nucleoside inhibitors of human norovirus polymerase |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9864251/ https://www.ncbi.nlm.nih.gov/pubmed/36680114 http://dx.doi.org/10.3390/v15010074 |
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