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Structural investigations on novel non-nucleoside inhibitors of human norovirus polymerase

Giancotti, Gilda, Nannetti, Giulio ORCID:, Padalino, Gilda, Landini, Martina, Santos-Ferreira, Nanci, Van Dycke, Jana, Naccarato, Valentina, Patel, Usheer, Silvestri, Romano, Neyts, Johan, Gozalbo-Rovira, Roberto, Rodríguez-Díaz, Jésus, Rocha-Pereira, Joana, Brancale, Andrea ORCID:, Ferla, Salvatore ORCID: and Bassetto, Marcella ORCID: 2022. Structural investigations on novel non-nucleoside inhibitors of human norovirus polymerase. Viruses 15 (1) , 74. 10.3390/v15010074

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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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Pharmacy
Additional Information: License information from Publisher: LICENSE 1: URL:, Type: open-access
Publisher: MDPI
Date of First Compliant Deposit: 6 January 2023
Date of Acceptance: 21 December 2022
Last Modified: 07 May 2023 05:14

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