Derudas_J Med Chem-Revised.pdf (3.05 MB)
Virtual Screening of acyclovir derivatives as potential antiviral agents: design, synthesis, and biological evaluation of new acyclic nucleoside ProTides
journal contribution
posted on 2023-06-09, 08:04 authored by Marco Derudas, Christophe Vanpouille, Davide Carta, Sonia Zicari, Graciela Andrei, Robert Snoeck, Andrea Brancale, Leonid Margolis, Jan Balzarini, Christopher McGuiganFollowing our findings on the anti-human immunodeficiency virus (HIV) activity of acyclovir (ACV) phosphate prodrugs, we herein report the ProTide approach applied to a series of acyclic nucleosides aimed at the identification of novel and selective antiviral, in particular anti-HIV agents. Acyclic nucleoside analogues used in this study were identified through a virtual screening using HIV-reverse transcriptase (RT), adenylate/guanylate kinase, and human DNA polymerase ?. A total of 39 new phosphate prodrugs were synthesized and evaluated against HIV-1 (in vitro and ex vivo human tonsillar tissue system) and human herpes viruses. Several ProTide compounds showed substantial potency against HIV-1 at low micromolar range while the parent nucleosides were not effective. Also, pronounced inhibition of herpesvirus replication was observed. A carboxypeptidase-mediated hydrolysis study was performed for a selection of compounds to assess the formation of putative metabolites and support the biological activity observed.
History
Publication status
- Published
File Version
- Accepted version
Journal
Journal of Medicinal ChemistryISSN
0022-2623Publisher
American Chemical SocietyExternal DOI
Issue
18Volume
60Page range
7876-7896Department affiliated with
- Chemistry Publications
Research groups affiliated with
- Sussex Drug Discovery Centre Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2017-10-24First Open Access (FOA) Date
2018-08-22First Compliant Deposit (FCD) Date
2017-09-25Usage metrics
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