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Structural Investigations on Novel Non-Nucleoside Inhibitors of Human Norovirus Polymerase

Gilda Giancotti Orcid Logo, Giulio Nannetti Orcid Logo, Gilda Padalino, Martina Landini, Nanci Santos-Ferreira Orcid Logo, Jana Van Dycke Orcid Logo, Valentina Naccarato, Usheer Patel, Romano Silvestri Orcid Logo, Johan Neyts Orcid Logo, Roberto Gozalbo-Rovira Orcid Logo, Jésus Rodríguez-Díaz Orcid Logo, Joana Rocha-Pereira Orcid Logo, Andrea Brancale Orcid Logo, Salvatore Ferla Orcid Logo, Marcella Bassetto

Viruses, Volume: 15, Issue: 1, Start page: 74

Swansea University Authors: Giulio Nannetti Orcid Logo, Salvatore Ferla Orcid Logo, Marcella Bassetto

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DOI (Published version): 10.3390/v15010074

Abstract

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...

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Published in: Viruses
ISSN: 1999-4915
Published: MDPI AG 2022
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URI: https://cronfa.swan.ac.uk/Record/cronfa62577
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spelling 2023-02-27T16:11:54.0141211 v2 62577 2023-02-06 Structural Investigations on Novel Non-Nucleoside Inhibitors of Human Norovirus Polymerase 8d6b68ac6d8a7ab60eb04cae67116565 0000-0003-3227-1537 Giulio Nannetti Giulio Nannetti true false d4c62248f510e3b221916989a7bbe6a6 0000-0002-5918-9237 Salvatore Ferla Salvatore Ferla true false b97beeed16f8e0524551233ade909565 Marcella Bassetto Marcella Bassetto true false 2023-02-06 PHAR 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. Journal Article Viruses 15 1 74 MDPI AG 1999-4915 human norovirus; RdRp inhibitors; computer-aided drug design 27 12 2022 2022-12-27 10.3390/v15010074 COLLEGE NANME Pharmacy COLLEGE CODE PHAR Swansea University G.G. was supported by the Wellcome Trust through an ISSF3 Translational Kickstart Award. S.F. was supported by the Sêr Cymru II programme which is part-funded by Cardiff and Swansea Universities, and the European Regional Development Fund through the Welsh Government. 2023-02-27T16:11:54.0141211 2023-02-06T08:32:58.8116091 Faculty of Science and Engineering School of Engineering and Applied Sciences - Chemistry Gilda Giancotti 0000-0002-6326-069x 1 Giulio Nannetti 0000-0003-3227-1537 2 Gilda Padalino 3 Martina Landini 4 Nanci Santos-Ferreira 0000-0003-4995-5580 5 Jana Van Dycke 0000-0003-1632-3499 6 Valentina Naccarato 7 Usheer Patel 8 Romano Silvestri 0000-0003-2489-0178 9 Johan Neyts 0000-0002-0033-7514 10 Roberto Gozalbo-Rovira 0000-0003-3427-3800 11 Jésus Rodríguez-Díaz 0000-0002-9698-7684 12 Joana Rocha-Pereira 0000-0001-8299-3787 13 Andrea Brancale 0000-0002-9728-3419 14 Salvatore Ferla 0000-0002-5918-9237 15 Marcella Bassetto 16 62577__26470__7eee4e3333274a6e96037b2a9d2f9b63.pdf 62577.pdf 2023-02-06T08:35:34.9142802 Output 8314388 application/pdf Version of Record true This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license true eng https://creativecommons.org/licenses/by/4.0/
title Structural Investigations on Novel Non-Nucleoside Inhibitors of Human Norovirus Polymerase
spellingShingle Structural Investigations on Novel Non-Nucleoside Inhibitors of Human Norovirus Polymerase
Giulio Nannetti
Salvatore Ferla
Marcella Bassetto
title_short 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_sort Structural Investigations on Novel Non-Nucleoside Inhibitors of Human Norovirus Polymerase
author_id_str_mv 8d6b68ac6d8a7ab60eb04cae67116565
d4c62248f510e3b221916989a7bbe6a6
b97beeed16f8e0524551233ade909565
author_id_fullname_str_mv 8d6b68ac6d8a7ab60eb04cae67116565_***_Giulio Nannetti
d4c62248f510e3b221916989a7bbe6a6_***_Salvatore Ferla
b97beeed16f8e0524551233ade909565_***_Marcella Bassetto
author Giulio Nannetti
Salvatore Ferla
Marcella Bassetto
author2 Gilda Giancotti
Giulio Nannetti
Gilda Padalino
Martina Landini
Nanci Santos-Ferreira
Jana Van Dycke
Valentina Naccarato
Usheer Patel
Romano Silvestri
Johan Neyts
Roberto Gozalbo-Rovira
Jésus Rodríguez-Díaz
Joana Rocha-Pereira
Andrea Brancale
Salvatore Ferla
Marcella Bassetto
format Journal article
container_title Viruses
container_volume 15
container_issue 1
container_start_page 74
publishDate 2022
institution Swansea University
issn 1999-4915
doi_str_mv 10.3390/v15010074
publisher MDPI AG
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Chemistry{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Chemistry
document_store_str 1
active_str 0
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.
published_date 2022-12-27T04:22:17Z
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score 11.016235

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