tetano
Editor, Senior Moderator
Antiviral Res. 2012 Jan 28. [Epub ahead of print]
Synthesis and biological evaluation of pyrimidine nucleoside monophosphate prodrugs targeted against influenza virus.
Meneghesso S, Vanderlinden E, Stevaert A, McGuigan C, Balzarini J, Naesens L.
Source
Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
Abstract
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, EC(99)=49?38μM and 23b, EC(99)⩾81μM) while the corresponding nucleoside analogue (2'-fluoro-2'-deoxyuridine) was inactive. Thus, at least in these cases the poor antiviral activity of the uridine analogues may be ascribed to poor phosphorylation.
Copyright ? 2012. Published by Elsevier B.V.
PMID:
22306172
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/22306172
Synthesis and biological evaluation of pyrimidine nucleoside monophosphate prodrugs targeted against influenza virus.
Meneghesso S, Vanderlinden E, Stevaert A, McGuigan C, Balzarini J, Naesens L.
Source
Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
Abstract
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, EC(99)=49?38μM and 23b, EC(99)⩾81μM) while the corresponding nucleoside analogue (2'-fluoro-2'-deoxyuridine) was inactive. Thus, at least in these cases the poor antiviral activity of the uridine analogues may be ascribed to poor phosphorylation.
Copyright ? 2012. Published by Elsevier B.V.
PMID:
22306172
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/22306172