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Phosphoramidate Dinucleosides as Hepatitis C Virus Polymerase Inhibitors

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journal contribution
posted on 25.09.2008, 00:00 by Ivan Zlatev, Hélène Dutartre, Ivan Barvik, Johan Neyts, Bruno Canard, Jean-Jacques Vasseur, Karine Alvarez, François Morvan
GC dinucleosides exhibiting a phosphoramidate internucleosidic linkage with neutral, amphiphile, positively or negatively charged side chains were synthesized. Their potential inhibitory effect on the hepatitis C virus (HCV) NS5B polymerase was evaluated in vitro and in HCV replicon containing cells. Whereas the amphiphile and the positively charged analogues were found to be inactive, the neutral (1) and the negatively charged (4) ones inhibited enzyme activity when tested as a diastereoisomeric mixture. The most potent inhibitor proved to be the Sp isomer of the 5′-thiophosphorylated dinucleotide bearing the carboxylic side chain (8) (IC50 of 25 μM in vitro and an EC50 of 9 μM in HCV subgenomic replicon). Molecular modeling suggests that the phosphoramidate dinucleoside (8) is stabilized in the active site by interactions with magnesium ions and lysine and arginine residues of the polymerase.