Derudas, Marco, Vanpouille, Christophe, Carta, Davide, Zicari, Sonia, Andrei, Graciela, Snoeck, Robert, Brancale, Andrea, Margolis, Leonid, Balzarini, Jan and McGuigan, Christopher (2017) Virtual Screening of acyclovir derivatives as potential antiviral agents: design, synthesis, and biological evaluation of new acyclic nucleoside ProTides. Journal of Medicinal Chemistry, 60 (18). pp. 7876-7896. ISSN 0022-2623

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Abstract

Following 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 γ. 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.

Item Type:	Article
Schools and Departments:	School of Life Sciences > Chemistry
Research Centres and Groups:	Sussex Drug Discovery Centre
Depositing User:	Marco Derudas
Date Deposited:	24 Oct 2017 13:47
Last Modified:	18 Jul 2019 15:30
URI:	http://sro.sussex.ac.uk/id/eprint/70331

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