Journal
ANTIVIRAL RESEARCH
Volume 94, Issue 1, Pages 35-43Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.antiviral.2012.01.007
Keywords
Uridine-based nucleoside analogues; ProTide; RNA polymerase; Carboxypeptidase Y
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Funding
- Katholieke Universiteit Leuven
- Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO) [9.0188.07]
- Geconcerteerde Onderzoeksacties [GOA/10/014]
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Uridine-based nucleoside analogues have often been found to have relatively poor antiviral activity. Enzymatic assays, evaluating inhibition of influenza virus RNA polymerase, revealed that some uridine triphosphate derivatives displayed inhibitory activity on UTP incorporation into viral RNA. Here we report the synthesis, antiviral activity and enzymatic evaluation of novel ProTides designed to deliver the activated (monophosphorylated) uridine analogues inside the influenza virus-infected cells. After evaluation of the activation profile we identified two ProTides with moderate antiviral activity in MDCK cells (23a, EC99 = 49 +/- 38 mu M and 23b, EC99 >= 81 mu M) while the corresponding nucleoside analogue (2'-flouro-2'-deoxyuridine) was inactive. Thus, at least in these cases the poor antiviral activity of the uridine analogues may be ascribed to poor phosphorylation. (c) 2012 Elsevier B.V. All rights reserved.
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