Journal article 775 views 61 downloads
Structural Investigations on Novel Non-Nucleoside Inhibitors of Human Norovirus Polymerase
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Giulio Nannetti ,
Gilda Padalino,
Martina Landini,
Nanci Santos-Ferreira ,
Jana Van Dycke ,
Valentina Naccarato,
Usheer Patel,
Romano Silvestri ,
Johan Neyts ,
Roberto Gozalbo-Rovira ,
Jésus Rodríguez-Díaz ,
Joana Rocha-Pereira ,
Andrea Brancale ,
Salvatore Ferla ,
Marcella Bassetto
Viruses, Volume: 15, Issue: 1, Start page: 74
Swansea University Authors:
Giulio Nannetti , Salvatore Ferla , Marcella Bassetto
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DOI (Published version): 10.3390/v15010074
Abstract
Human norovirus is the first cause of foodborne disease worldwide, leading to extensive outbreaks of acute gastroenteritis, and causing around 200,000 children to die annually in developing countries. No specific vaccines or antiviral agents are currently available, with therapeutic options limited...
| Published in: | Viruses |
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| ISSN: | 1999-4915 |
| Published: |
MDPI AG
2022
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| Online Access: |
Check full text
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa62577 |
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| Abstract: |
Human norovirus is the first cause of foodborne disease worldwide, leading to extensive outbreaks of acute gastroenteritis, and causing around 200,000 children to die annually in developing countries. No specific vaccines or antiviral agents are currently available, with therapeutic options limited to supportive care to prevent dehydration. The infection can become severe and lead to life-threatening complications in young children, the elderly and immunocompromised individuals, leading to a clear need for antiviral agents, to be used as treatments and as prophylactic measures in case of outbreaks. Due to the key role played by the viral RNA-dependent RNA polymerase (RdRp) in the virus life cycle, this enzyme is a promising target for antiviral drug discovery. In previous studies, following in silico investigations, we identified different small-molecule inhibitors of this enzyme. In this study, we rationally modified five identified scaffolds, to further explore structure–activity relationships, and to enhance binding to the RdRp. The newly designed compounds were synthesized according to multiple-step synthetic routes and evaluated for their inhibition of the enzyme in vitro. New inhibitors with low micromolar inhibitory activity of the RdRp were identified, which provide a promising basis for further hit-to-lead optimization. |
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| Keywords: |
human norovirus; RdRp inhibitors; computer-aided drug design |
| College: |
Faculty of Science and Engineering |
| Funders: |
G.G. was supported by the Wellcome Trust through an ISSF3 Translational Kickstart Award. S.F. was supported by the Sêr Cymru II programme which is part-funded by Cardiff and Swansea Universities, and the European Regional Development Fund through the Welsh Government. |
| Issue: |
1 |
| Start Page: |
74 |