5 years ago

Discovery of Novel Nucleotide Prodrugs with Improved Potency Against HCV Variants Carrying NS5B S282T Mutation

Discovery of Novel Nucleotide Prodrugs with Improved Potency Against HCV Variants Carrying NS5B S282T Mutation
Xiaoliang Jin, Liang Dai, Haoliang Yuan, Hongbin Sun, Wenfeng Zhao, Xiao-Wen Yang, Lan Yao, Guangji Wang, Sheng-Qi Yu, Le Zhen, Xiaoan Wen
Resistant HCV variants carrying NS5B S282T mutation confer reduced sensitivity to sofosbuvir, the sole marketed NS5B polymerase inhibitor. On the basis of the finding that 2′-α-F-2′-β-C-methylcytidine 5′-triphosphate (8) was more potent than sofosbuvir’s active metabolite on inhibition of both wild-type and S282T mutant polymerase, a dual-prodrug approach has been established. Twenty-nine phosphoramidates with N4-modified cytosine were designed, synthesized, and evaluated for anti-HCV activity. The results showed that compounds 4c4e and 4m (EC50 = 0.19–0.25 μM) exhibited comparable potency to that of sofosbuvir (EC50 = 0.15 μM) on inhibition of wild-type replicons. Notably, 4c (EC50 = 0.366 μM) was 1.5-fold more potent than sofosbuvir (EC50 = 0.589 μM) on inhibition of S282T mutant replicons. In vitro metabolic studies disclosed the possible metabolic pathways of 4c. The toxicity study results indicated a good safety profile of 4c. Together, 4c4e and 4m hold promise for drug development for the treatment of HCV infection, especially the resistant variants with NS5B S282T mutation.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00262

DOI: 10.1021/acs.jmedchem.7b00262

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