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New dengue virus inhibitors targeting NS3-NS5 interaction identified by in silico screening

Giulio Nannetti Orcid Logo, Beatrice Mercorelli, Alessandro Bazzacco, Nicolò Santi, Marta Celegato, Salvatore Ferla Orcid Logo, Mattia Sturlese, Niklaas J. Buurma, Andrea Brancale, Arianna Loregian

Frontiers in Microbiology, Volume: 16, Start page: 1663404

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

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    © 2025 Nannetti, Mercorelli, Bazzacco, Santi, Celegato, Ferla, Sturlese, Buurma, Brancale and Loregian. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).

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DOI (Published version): 10.3389/fmicb.2025.1663404

Abstract

Dengue virus (DENV) poses a major public health concern as it is responsible for approximately 100 million human infections annually. Since no antiviral drugs are currently available to treat DENV infection, the development of effective therapeutic strategies is urgently needed. For anti-DENV drug d...

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Published in: Frontiers in Microbiology
ISSN: 1664-302X
Published: Frontiers Media SA 2025
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URI: https://cronfa.swan.ac.uk/Record/cronfa70866
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spelling 2025-11-10T15:43:45.1411498 v2 70866 2025-11-07 New dengue virus inhibitors targeting NS3-NS5 interaction identified by in silico screening 8d6b68ac6d8a7ab60eb04cae67116565 0000-0003-3227-1537 Giulio Nannetti Giulio Nannetti true false d4c62248f510e3b221916989a7bbe6a6 0000-0002-5918-9237 Salvatore Ferla Salvatore Ferla true false 2025-11-07 MEDS Dengue virus (DENV) poses a major public health concern as it is responsible for approximately 100 million human infections annually. Since no antiviral drugs are currently available to treat DENV infection, the development of effective therapeutic strategies is urgently needed. For anti-DENV drug discovery, the interaction between DENV NS3 and NS5 proteins represents an attractive target, as it is essential for viral replication and is highly conserved across all DENV serotypes. In this study, we report two distinct virtual screenings of commercially available drug-like compounds, which were performed to identify inhibitors of the NS3-NS5 interaction. Both screening approaches led to the identification of hit compounds that were able to reduce NS3-NS5 binding in vitro in a dose-dependent manner, as measured by an ELISA-based assay. Moreover, the hits inhibited the replication of DENV-2 at low micromolar and non-cytotoxic concentrations. Among these, hit 3 exhibited the highest selectivity index and showed antiviral activity against all four DENV serotypes. Biophysical studies indicated that hit 3 exerts its antiviral activity by directly binding to NS5. Hit 3 was then selected for structure-activity relationship studies, leading to the identification of structural analogues that retained anti-DENV activity through the disruption of NS3-NS5 interaction. Overall, this study reports the identification of a series of novel chemical scaffolds endowed with pan-dengue antiviral activity, representing a promising foundation for the development of new anti-DENV agents. Journal Article Frontiers in Microbiology 16 1663404 Frontiers Media SA 1664-302X dengue virus inhibitors, NS3-NS5 interaction, dissociative inhibitors, protein-protein interaction, flavivirus, antiviral compounds 31 10 2025 2025-10-31 10.3389/fmicb.2025.1663404 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee This work was supported by Marie Skłodowska-Curie Individual Fellowship (MSC-IF, grant number 798105) to GN, by Wellcome Trust Translational Kickstart Award (ISSF3, grant number 518470) to GN, by University of Padua, Italy (STARS Co-Grant 2017 and PRID 2021) to BM, by EU funding within the NextGenerationEU-MUR PNRR Extended Partnership initiative on Emerging Infectious Diseases (Project no. PE00000007, INF-ACT) to AL, by Ministero dell’Università e della Ricerca, Italy (grants PRIN 2022-cod. 20223RYYFC and PRIN 2022 PNRR - cod. P20222YKP8) to AL, and by Associazione Italiana per la Ricerca sul Cancro, AIRC, Italy (grant IG 2021 - ID. 25899) to AL. Open Access funding provided by Universitá degli Studi di Padova | University of Padua, Open Science Committee. 2025-11-10T15:43:45.1411498 2025-11-07T14:51:02.5266138 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Pharmacy Giulio Nannetti 0000-0003-3227-1537 1 Beatrice Mercorelli 2 Alessandro Bazzacco 3 Nicolò Santi 4 Marta Celegato 5 Salvatore Ferla 0000-0002-5918-9237 6 Mattia Sturlese 7 Niklaas J. Buurma 8 Andrea Brancale 9 Arianna Loregian 10 70866__35591__50ec89157f034769a5f40dc342d4ef9e.pdf 70866.VOR.pdf 2025-11-10T15:41:57.6043592 Output 3086980 application/pdf Version of Record true © 2025 Nannetti, Mercorelli, Bazzacco, Santi, Celegato, Ferla, Sturlese, Buurma, Brancale and Loregian. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). true eng http://creativecommons.org/licenses/by/4.0/
title New dengue virus inhibitors targeting NS3-NS5 interaction identified by in silico screening
spellingShingle New dengue virus inhibitors targeting NS3-NS5 interaction identified by in silico screening
Giulio Nannetti
Salvatore Ferla
title_short New dengue virus inhibitors targeting NS3-NS5 interaction identified by in silico screening
title_full New dengue virus inhibitors targeting NS3-NS5 interaction identified by in silico screening
title_fullStr New dengue virus inhibitors targeting NS3-NS5 interaction identified by in silico screening
title_full_unstemmed New dengue virus inhibitors targeting NS3-NS5 interaction identified by in silico screening
title_sort New dengue virus inhibitors targeting NS3-NS5 interaction identified by in silico screening
author_id_str_mv 8d6b68ac6d8a7ab60eb04cae67116565
d4c62248f510e3b221916989a7bbe6a6
author_id_fullname_str_mv 8d6b68ac6d8a7ab60eb04cae67116565_***_Giulio Nannetti
d4c62248f510e3b221916989a7bbe6a6_***_Salvatore Ferla
author Giulio Nannetti
Salvatore Ferla
author2 Giulio Nannetti
Beatrice Mercorelli
Alessandro Bazzacco
Nicolò Santi
Marta Celegato
Salvatore Ferla
Mattia Sturlese
Niklaas J. Buurma
Andrea Brancale
Arianna Loregian
format Journal article
container_title Frontiers in Microbiology
container_volume 16
container_start_page 1663404
publishDate 2025
institution Swansea University
issn 1664-302X
doi_str_mv 10.3389/fmicb.2025.1663404
publisher Frontiers Media SA
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Pharmacy{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Pharmacy
document_store_str 1
active_str 0
description Dengue virus (DENV) poses a major public health concern as it is responsible for approximately 100 million human infections annually. Since no antiviral drugs are currently available to treat DENV infection, the development of effective therapeutic strategies is urgently needed. For anti-DENV drug discovery, the interaction between DENV NS3 and NS5 proteins represents an attractive target, as it is essential for viral replication and is highly conserved across all DENV serotypes. In this study, we report two distinct virtual screenings of commercially available drug-like compounds, which were performed to identify inhibitors of the NS3-NS5 interaction. Both screening approaches led to the identification of hit compounds that were able to reduce NS3-NS5 binding in vitro in a dose-dependent manner, as measured by an ELISA-based assay. Moreover, the hits inhibited the replication of DENV-2 at low micromolar and non-cytotoxic concentrations. Among these, hit 3 exhibited the highest selectivity index and showed antiviral activity against all four DENV serotypes. Biophysical studies indicated that hit 3 exerts its antiviral activity by directly binding to NS5. Hit 3 was then selected for structure-activity relationship studies, leading to the identification of structural analogues that retained anti-DENV activity through the disruption of NS3-NS5 interaction. Overall, this study reports the identification of a series of novel chemical scaffolds endowed with pan-dengue antiviral activity, representing a promising foundation for the development of new anti-DENV agents.
published_date 2025-10-31T05:31:53Z
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