Journal article 152 views 55 downloads
New dengue virus inhibitors targeting NS3-NS5 interaction identified by in silico screening
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Beatrice Mercorelli,
Alessandro Bazzacco,
Nicolò Santi,
Marta Celegato,
Salvatore Ferla ,
Mattia Sturlese,
Niklaas J. Buurma,
Andrea Brancale,
Arianna Loregian
Frontiers in Microbiology, Volume: 16, Start page: 1663404
Swansea University Authors:
Giulio Nannetti , Salvatore Ferla
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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...
| Published in: | Frontiers in Microbiology |
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| ISSN: | 1664-302X |
| Published: |
Frontiers Media SA
2025
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa70866 |
| 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 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. |
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| Keywords: |
dengue virus inhibitors, NS3-NS5 interaction, dissociative inhibitors, protein-protein interaction, flavivirus, antiviral compounds |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
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. |
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1663404 |