The application of the phosphoramidate ProTide approach confers micromolar potency against hepatitis C virus on inactive agent 4'-azidoinosine: kinase bypass on a dual base/sugar modified nucleoside.
Novel phosphoramidate ProTides derived from 4'-azidoinosine have been prepared and evaluated in the replicon assay against hepatitis C Virus (HCV). The parent nucleoside analogue is inactive in this assay, while the ProTides are active at low microM levels in some cases. This is a rare example of an inosine nucleoside analogue with potent antiviral activity and further supports the notion of ProTides as a drug discovery motif.
McGuigan
Christopher
C
Welsh School of Pharmacy, Cardiff University, Cardiff, UK. mcguigan@cardiff.ac.uk
Daverio
Felice
F
Nájera
Isabel
I
Martin
Joseph A
JA
Klumpp
Klaus
K
Smith
David B
DB
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001386:Azides / Q000138:chemical synthesis* / Q000737:chemistry; D055808:Drug Discovery; D016174:Hepacivirus / Q000187:drug effects*; D007288:Inosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry*; D010756:Phosphoric Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity
C542048:4'-azidoinosine; D000577:Amides; D000998:Antiviral Agents; D001386:Azides; D009705:Nucleosides; D010756:Phosphoric Acids; D007288:Inosine; C011067:phosphoramidic acid