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

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

doi:10.3390/microorganisms9091795

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

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

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

Swansea University Authors: Salvatore Ferla , 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
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa57742

first_indexed	2021-09-22T15:25:23Z
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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 Derivatives in which the terminal phenyl group has been replaced by an unsubstituted benzoxazole or indole, and the thioamide component of the amide-thioamide linker has been removed, showed promising results in inhibiting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. 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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 0000-0003-2283-3014 Ben Flude Ben Flude true false b97beeed16f8e0524551233ade909565 Marcella Bassetto Marcella Bassetto true false 2021-09-01 MEDS 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 Medical School COLLEGE CODE MEDS 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 0000-0003-2283-3014 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
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department_str	School of Engineering and Applied Sciences - Chemistry{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Chemistry
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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	2021-08-24T08:04:20Z
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Structure–Activity Relationship Studies on Novel Antiviral Agents for Norovirus Infections

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