Preclinical development of bicyclic nucleoside analogues as potent and selective inhibitors of varicella zoster virus

McGuigan, Christopher ORCID: https://orcid.org/0000-0001-8409-710X, Pathirana, Ranjith N., Migliore, Marco, Adak, Rina, Luoni, Giovanna maria, Jones, Arwyn Tomos ORCID: https://orcid.org/0000-0003-2781-8905, Díez-Torrubia, Alberto, Camarasa, Maria-Jose, Velázquez, Sonsoles, Henson, Geoffrey, Verbeken, Erik, Sienaer, Rebecca, Naesens, Lieve, Snoeck, Robert, Andrei, Graciela and Balzarini, Jan 2007. Preclinical development of bicyclic nucleoside analogues as potent and selective inhibitors of varicella zoster virus. Journal of Antimicrobial Chemotherapy 60 (6) , pp. 1316-1330. 10.1093/jac/dkm376

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Abstract

Objectives To progress the anti-varicella-zoster-virus (VZV) aryl bicyclic nucleoside analogues (BCNAs) to the point of Phase 1 clinical trial for herpes zoster. Methods A new chromatography-free synthetic access to the lead anti-VZV aryl BCNAs is reported. The anti-VZV activity of lead Cf1743 was evaluated in monolayer cell cultures and organotypic epithelial raft cultures of primary human keratinocytes. Oral dosing in rodents and preliminary pharmacokinetics assessment was made, followed by an exploration of alternative formulations and the preparation of pro-drugs. We also studied uptake into cells of both parent drug and pro-drug using fluorescent microscopy and biological assays. Results Cf1743 proved to be significantly more potent than all reference anti-VZV compounds as measured either by inhibition of infectious virus particles and/or by viral DNA load. However, the very low water solubility of this compound gave poor oral bioavailability (?14%). A Captisol

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	Antiviral ; VZV ; BCNAs ; Herpes
Publisher:	Oxford University Press
ISSN:	0305-7453
Last Modified:	17 Oct 2022 08:45
URI:	https://orca.cardiff.ac.uk/id/eprint/977

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