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Design, synthesis and biological evaluation of novel acyclovir ProTides

Derudas, Marco, McGuigan, Christopher, Brancale, Andrea, Bugert, Joachim Jakob, Andrei, G., Snoeck, R. and Balzarini, J. 2008. Design, synthesis and biological evaluation of novel acyclovir ProTides. Antiviral Research 78 (2) , A55-A56. 10.1016/j.antiviral.2008.01.116

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Abstract

Acyclovir and its prodrug valacyclovir are currently the treatments of choice for herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. Intracellular conversion of acyclovir to its active triphosphate form is severely limited by the first phosphorylation step, which is carried out by a herpes virus encoded thymidine kinase (Elion et al., 1977). Further conversions to the di- and triphosphate are mediated by cellular guanosine monophosphate kinase and nucleoside diphosphate kinase respectively. Importantly, the activation of the compound by the viral nucleoside kinase is a target for drug resistance in both HSV and VZV strains (Larder et al., 1983). Our phosphoramidate ProTide approach was applied to acyclovir as a means to bypass the limiting step of its activation. However, no significant improvement in antiviral activity was observed (McGuigan et al., 2000). In the present work, a new series of optimised acyclovir ProTides with an enhanced biological profile is reported (Fig. 1).

Item Type: Article
Status: Published
Schools: Medicine
Pharmacy
Systems Immunity Research Institute (SIURI)
Publisher: Elsevier
ISSN: 0166-3542
Last Modified: 18 Oct 2017 13:08
URI: http://orca-mwe.cf.ac.uk/id/eprint/6491

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