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Structure–Activity Relationship Studies on Novel Antiviral Agents for Norovirus Infections

Salvatore Ferla Orcid Logo, Carmine Varricchio, William Knight, Pui Kei Ho, Fabiana Saporito, Beatrice Tropea, Giulio Fagan, Ben Flude, Federica Bevilacqua, Nanci Santos-Ferreira, Jana Van Dycke, Johan Neyts, Andrea Brancale, Joana Rocha-Pereira, Marcella Bassetto

Microorganisms, Volume: 9, Issue: 9, Start page: 1795

Swansea University Authors: Salvatore Ferla Orcid Logo, Ben Flude, Marcella Bassetto

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DOI (Published version): 10.3390/microorganisms9091795

Abstract

Human norovirus is the leading cause of acute gastroenteritis worldwide, affecting every year 685 million people. Norovirus outbreaks are associated with very significant economic losses, with an estimated societal cost of 60 billion USD per year. Despite this, no therapeutic options or vaccines are...

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Published in: Microorganisms
ISSN: 2076-2607
Published: MDPI AG 2021
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URI: https://cronfa.swan.ac.uk/Record/cronfa57742
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Norovirus outbreaks are associated with very significant economic losses, with an estimated societal cost of 60 billion USD per year. Despite this, no therapeutic options or vaccines are currently available to treat or prevent this infection. An antiviral therapy that can be used as treatment and as a prophylactic measure in the case of outbreaks is urgently needed. We previously described the computer-aided design and synthesis of novel small-molecule agents able to inhibit the replication of human norovirus in cell-based systems. These compounds are non-nucleoside inhibitors of the viral polymerase and are characterized by a terminal para-substituted phenyl group connected to a central phenyl ring by an amide-thioamide linker, and a terminal thiophene ring. Here we describe new modifications of these scaffolds focused on exploring the role of the substituent at the para position of the terminal phenyl ring and on removing the thioamide portion of the amide-thioamide linker, to further explore structure-activity relationships (SARs) and improve antiviral properties. According to three to four-step synthetic routes, we prepared thirty novel compounds, which were then evaluated against the replication of both murine (MNV) and human (HuNoV) norovirus in cells. Derivatives in which the terminal phenyl group has been replaced by an unsubstituted benzoxazole or indole, and the thioamide component of the amide-thioamide linker has been removed, showed promising results in inhibiting HuNoV replication at low micromolar concentrations. Particularly, compound 28 was found to have an EC50 against HuNoV of 0.9 &#xB5;M. 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spelling 2021-10-12T17:26:12.3054265 v2 57742 2021-09-01 Structure–Activity Relationship Studies on Novel Antiviral Agents for Norovirus Infections d4c62248f510e3b221916989a7bbe6a6 0000-0002-5918-9237 Salvatore Ferla Salvatore Ferla true false 436efd85ed59ff6f05f1f1218cbab308 Ben Flude Ben Flude true false b97beeed16f8e0524551233ade909565 Marcella Bassetto Marcella Bassetto true false 2021-09-01 PHAR Human norovirus is the leading cause of acute gastroenteritis worldwide, affecting every year 685 million people. Norovirus outbreaks are associated with very significant economic losses, with an estimated societal cost of 60 billion USD per year. Despite this, no therapeutic options or vaccines are currently available to treat or prevent this infection. An antiviral therapy that can be used as treatment and as a prophylactic measure in the case of outbreaks is urgently needed. We previously described the computer-aided design and synthesis of novel small-molecule agents able to inhibit the replication of human norovirus in cell-based systems. These compounds are non-nucleoside inhibitors of the viral polymerase and are characterized by a terminal para-substituted phenyl group connected to a central phenyl ring by an amide-thioamide linker, and a terminal thiophene ring. Here we describe new modifications of these scaffolds focused on exploring the role of the substituent at the para position of the terminal phenyl ring and on removing the thioamide portion of the amide-thioamide linker, to further explore structure-activity relationships (SARs) and improve antiviral properties. According to three to four-step synthetic routes, we prepared thirty novel compounds, which were then evaluated against the replication of both murine (MNV) and human (HuNoV) norovirus in cells. Derivatives in which the terminal phenyl group has been replaced by an unsubstituted benzoxazole or indole, and the thioamide component of the amide-thioamide linker has been removed, showed promising results in inhibiting HuNoV replication at low micromolar concentrations. Particularly, compound 28 was found to have an EC50 against HuNoV of 0.9 µM. Although the most active novel derivatives were also associated with an increased cytotoxicity in the human cell line, these compounds represent a very promising starting point for the development of new analogues with reduced cytotoxicity and improved selectivity indexes. In addition, the experimental biological data have been used to create an initial 3D quantitative structure-activity relationship model, which could be used to guide the future design of novel potential anti-norovirus agents. Journal Article Microorganisms 9 9 1795 MDPI AG 2076-2607 antiviral agents; human norovirus; computer-aided drug design; SARs 24 8 2021 2021-08-24 10.3390/microorganisms9091795 COLLEGE NANME Pharmacy COLLEGE CODE PHAR Swansea University This research received no external funding. S.F. is supported by the Sêr Cymru II programme, which is part-funded by Swansea University and the European Regional Development Fund through the Welsh Government. B.M.F. is supported by an EPSRC PhD studentship (PHFS4CT). 2021-10-12T17:26:12.3054265 2021-09-01T10:17:09.8998294 Faculty of Science and Engineering School of Engineering and Applied Sciences - Chemistry Salvatore Ferla 0000-0002-5918-9237 1 Carmine Varricchio 2 William Knight 3 Pui Kei Ho 4 Fabiana Saporito 5 Beatrice Tropea 6 Giulio Fagan 7 Ben Flude 8 Federica Bevilacqua 9 Nanci Santos-Ferreira 10 Jana Van Dycke 11 Johan Neyts 12 Andrea Brancale 13 Joana Rocha-Pereira 14 Marcella Bassetto 15 57742__20972__c6461d7b260f4ab0b8e54995694edaca.pdf 57742.pdf 2021-09-22T16:24:52.5010113 Output 2284394 application/pdf Version of Record true © 2021 by the authors. 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 Structure–Activity Relationship Studies on Novel Antiviral Agents for Norovirus Infections
spellingShingle Structure–Activity Relationship Studies on Novel Antiviral Agents for Norovirus Infections
Salvatore Ferla
Ben Flude
Marcella Bassetto
title_short Structure–Activity Relationship Studies on Novel Antiviral Agents for Norovirus Infections
title_full Structure–Activity Relationship Studies on Novel Antiviral Agents for Norovirus Infections
title_fullStr Structure–Activity Relationship Studies on Novel Antiviral Agents for Norovirus Infections
title_full_unstemmed Structure–Activity Relationship Studies on Novel Antiviral Agents for Norovirus Infections
title_sort Structure–Activity Relationship Studies on Novel Antiviral Agents for Norovirus Infections
author_id_str_mv d4c62248f510e3b221916989a7bbe6a6
436efd85ed59ff6f05f1f1218cbab308
b97beeed16f8e0524551233ade909565
author_id_fullname_str_mv d4c62248f510e3b221916989a7bbe6a6_***_Salvatore Ferla
436efd85ed59ff6f05f1f1218cbab308_***_Ben Flude
b97beeed16f8e0524551233ade909565_***_Marcella Bassetto
author Salvatore Ferla
Ben Flude
Marcella Bassetto
author2 Salvatore Ferla
Carmine Varricchio
William Knight
Pui Kei Ho
Fabiana Saporito
Beatrice Tropea
Giulio Fagan
Ben Flude
Federica Bevilacqua
Nanci Santos-Ferreira
Jana Van Dycke
Johan Neyts
Andrea Brancale
Joana Rocha-Pereira
Marcella Bassetto
format Journal article
container_title Microorganisms
container_volume 9
container_issue 9
container_start_page 1795
publishDate 2021
institution Swansea University
issn 2076-2607
doi_str_mv 10.3390/microorganisms9091795
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 leading cause of acute gastroenteritis worldwide, affecting every year 685 million people. Norovirus outbreaks are associated with very significant economic losses, with an estimated societal cost of 60 billion USD per year. Despite this, no therapeutic options or vaccines are currently available to treat or prevent this infection. An antiviral therapy that can be used as treatment and as a prophylactic measure in the case of outbreaks is urgently needed. We previously described the computer-aided design and synthesis of novel small-molecule agents able to inhibit the replication of human norovirus in cell-based systems. These compounds are non-nucleoside inhibitors of the viral polymerase and are characterized by a terminal para-substituted phenyl group connected to a central phenyl ring by an amide-thioamide linker, and a terminal thiophene ring. Here we describe new modifications of these scaffolds focused on exploring the role of the substituent at the para position of the terminal phenyl ring and on removing the thioamide portion of the amide-thioamide linker, to further explore structure-activity relationships (SARs) and improve antiviral properties. According to three to four-step synthetic routes, we prepared thirty novel compounds, which were then evaluated against the replication of both murine (MNV) and human (HuNoV) norovirus in cells. Derivatives in which the terminal phenyl group has been replaced by an unsubstituted benzoxazole or indole, and the thioamide component of the amide-thioamide linker has been removed, showed promising results in inhibiting HuNoV replication at low micromolar concentrations. Particularly, compound 28 was found to have an EC50 against HuNoV of 0.9 µM. Although the most active novel derivatives were also associated with an increased cytotoxicity in the human cell line, these compounds represent a very promising starting point for the development of new analogues with reduced cytotoxicity and improved selectivity indexes. In addition, the experimental biological data have been used to create an initial 3D quantitative structure-activity relationship model, which could be used to guide the future design of novel potential anti-norovirus agents.
published_date 2021-08-24T04:13:42Z
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