Paper Citing NAMD - Abstract
Priet, Stephane; Zlatev, Ivan; Barvik, Ivan, Jr.; Geerts, Katrien; Leyssen, Pieter; Neyts, Johan; Dutartre, Helene; Canard, Bruno; Vasseur, Jean-Jacques; Morvan, Francois; Alvarez, Karine
3 '-Deoxy Phosphoramidate Dinucleosides as Improved Inhibitors of Hepatitis C Virus Subgenomic Replicon and NS5B Polymerase Activity
JOURNAL OF MEDICINAL CHEMISTRY, 53:6608-6617, SEP 23 2010
Phosphoramidate dinucleosides named "GC 3'-OH" series, carrying various phosphoramidate linkages have been previously reported as hepatitis C virus (HCV) inhibitors. To enhance the efficacy of these dinucleotides, we synthesized a novel "GC 3'-OH series as potential chain terminators. We showed that their inhibition potency is strongly increased by the introduction of novel neutral and his-negatively charged phosphoramidate side chains. Their inhibitory effect on HCV NS5B polymerise was evaluated in vitro and in HCV subgenomic replicon containing Huh-6 cells. As expected, 3'-H compounds are more potent than their 3'-OH counterparts to inhibit HCV polymerise activity. The most potent inhibitor, a 5'-phosphorylated dinucleotide bearing a his-negatively charged amino side chain (7), exhibits an IC(50) value of 8 mu M in vitro and EC(50) value of 2.6 mu M in the HCV subgenomic replicon system. A molecular structure model is presented to propose an interpretation of the gain afforded by the of 3'-H-cytidine modification.
