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 ORCID: https://orcid.org/0000-0002-9728-3419, Margolis, Leonid, Balzarini, Jan and McGuigan, Christopher ORCID: https://orcid.org/0000-0001-8409-710X 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:	17 Feb 2024 14:43
URI:	https://orca.cardiff.ac.uk/id/eprint/120522

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