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Virtual screening of acyclovir derivatives as potential antiviral agents: design, synthesis, and biological evaluation of new acyclic nucleoside protides

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. 10.1021/acs.jmedchem.7b01009

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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
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: American Chemical Society
ISSN: 0022-2623
Date of First Compliant Deposit: 11 March 2019
Date of Acceptance: 22 August 2017
Last Modified: 29 Jun 2019 15:39
URI: http://orca-mwe.cf.ac.uk/id/eprint/120522

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