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Rational design of novel nucleoside analogues reveals potent antiviral agents for EV71

Martina Salerno Salerno, Carmine Varricchio, Federica Bevilacqua, Dirk Jochmans, Johan Neyts, Andrea Brancale, Salvatore Ferla Orcid Logo, Marcella Bassetto

European Journal of Medicinal Chemistry, Volume: 246, Start page: 114942

Swansea University Authors: Martina Salerno Salerno, Salvatore Ferla Orcid Logo, Marcella Bassetto

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DOI (Published version): 10.1016/j.ejmech.2022.114942

Abstract

Different viruses belonging to distinct viral families, such as enterovirus 71, rely on the host methyltransferase METTL3 for the completion of fundamental cytoplasmic stages of their life cycle. Modulation of the activity of this enzyme could therefore provide a broad-spectrum approach to interfere...

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Published in: European Journal of Medicinal Chemistry
ISSN: 0223-5234
Published: Elsevier BV 2023
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URI: https://cronfa.swan.ac.uk/Record/cronfa62048
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spelling 2022-12-12T14:07:59.9715588 v2 62048 2022-11-25 Rational design of novel nucleoside analogues reveals potent antiviral agents for EV71 0ecd6f5c438caf31402b33306fd043ec Martina Salerno Salerno Martina Salerno Salerno true false d4c62248f510e3b221916989a7bbe6a6 0000-0002-5918-9237 Salvatore Ferla Salvatore Ferla true false b97beeed16f8e0524551233ade909565 Marcella Bassetto Marcella Bassetto true false 2022-11-25 CHEM Different viruses belonging to distinct viral families, such as enterovirus 71, rely on the host methyltransferase METTL3 for the completion of fundamental cytoplasmic stages of their life cycle. Modulation of the activity of this enzyme could therefore provide a broad-spectrum approach to interfere with viral infections caused by viruses that depend on its activity for the completion of their viral cycle. With the aim to identify antiviral therapeutics with this effect, a series of new nucleoside analogues was rationally designed to act as inhibitors of human METTL3, as a novel approach to interfere with a range of viral infections. Guided by molecular docking studies on the SAM binding pocket of the enzyme, 24 compounds were prepared following multiple-step synthetic protocols, and evaluated for their ability to interfere with the replication of different viruses in cell-based systems, and to directly inhibit the activity of METTL3. While different molecules displayed moderate inhibition of the human methyltransferase in vitro, multiple novel, potent and selective inhibitors of enterovirus 71 were identified. Journal Article European Journal of Medicinal Chemistry 246 114942 Elsevier BV 0223-5234 15 1 2023 2023-01-15 10.1016/j.ejmech.2022.114942 COLLEGE NANME Chemistry COLLEGE CODE CHEM Swansea University SU Library paid the OA fee (TA Institutional Deal) This research was partly funded by the Sˆer Cymru II programme, part-funded by Cardiff and Swansea Universities and the European Regional Development Fund through the Welsh Government. 2022-12-12T14:07:59.9715588 2022-11-25T14:15:15.8681109 Faculty of Science and Engineering School of Engineering and Applied Sciences - Chemistry Martina Salerno Salerno 1 Carmine Varricchio 2 Federica Bevilacqua 3 Dirk Jochmans 4 Johan Neyts 5 Andrea Brancale 6 Salvatore Ferla 0000-0002-5918-9237 7 Marcella Bassetto 8 62048__26066__4ef09e1387924a2c831934c090ff2851.pdf 62048_VoR.pdf 2022-12-12T14:06:32.2002762 Output 8386042 application/pdf Version of Record true © 2022 The Authors. This is an open access article under the CC BY-NC-ND license true eng http://creativecommons.org/licenses/by-nc-nd/4.0/
title Rational design of novel nucleoside analogues reveals potent antiviral agents for EV71
spellingShingle Rational design of novel nucleoside analogues reveals potent antiviral agents for EV71
Martina Salerno Salerno
Salvatore Ferla
Marcella Bassetto
title_short Rational design of novel nucleoside analogues reveals potent antiviral agents for EV71
title_full Rational design of novel nucleoside analogues reveals potent antiviral agents for EV71
title_fullStr Rational design of novel nucleoside analogues reveals potent antiviral agents for EV71
title_full_unstemmed Rational design of novel nucleoside analogues reveals potent antiviral agents for EV71
title_sort Rational design of novel nucleoside analogues reveals potent antiviral agents for EV71
author_id_str_mv 0ecd6f5c438caf31402b33306fd043ec
d4c62248f510e3b221916989a7bbe6a6
b97beeed16f8e0524551233ade909565
author_id_fullname_str_mv 0ecd6f5c438caf31402b33306fd043ec_***_Martina Salerno Salerno
d4c62248f510e3b221916989a7bbe6a6_***_Salvatore Ferla
b97beeed16f8e0524551233ade909565_***_Marcella Bassetto
author Martina Salerno Salerno
Salvatore Ferla
Marcella Bassetto
author2 Martina Salerno Salerno
Carmine Varricchio
Federica Bevilacqua
Dirk Jochmans
Johan Neyts
Andrea Brancale
Salvatore Ferla
Marcella Bassetto
format Journal article
container_title European Journal of Medicinal Chemistry
container_volume 246
container_start_page 114942
publishDate 2023
institution Swansea University
issn 0223-5234
doi_str_mv 10.1016/j.ejmech.2022.114942
publisher Elsevier BV
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 Different viruses belonging to distinct viral families, such as enterovirus 71, rely on the host methyltransferase METTL3 for the completion of fundamental cytoplasmic stages of their life cycle. Modulation of the activity of this enzyme could therefore provide a broad-spectrum approach to interfere with viral infections caused by viruses that depend on its activity for the completion of their viral cycle. With the aim to identify antiviral therapeutics with this effect, a series of new nucleoside analogues was rationally designed to act as inhibitors of human METTL3, as a novel approach to interfere with a range of viral infections. Guided by molecular docking studies on the SAM binding pocket of the enzyme, 24 compounds were prepared following multiple-step synthetic protocols, and evaluated for their ability to interfere with the replication of different viruses in cell-based systems, and to directly inhibit the activity of METTL3. While different molecules displayed moderate inhibition of the human methyltransferase in vitro, multiple novel, potent and selective inhibitors of enterovirus 71 were identified.
published_date 2023-01-15T04:21:21Z
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