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Design, synthesis and biological evaluation of novel acyclovir ProTides

Derudas, Marco, McGuigan, Christopher ORCID:, Brancale, Andrea ORCID:, Bugert, Joachim Jakob ORCID:, 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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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
Systems Immunity Research Institute (SIURI)
Publisher: Elsevier
ISSN: 0166-3542
Last Modified: 17 Oct 2022 09:59

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