A Cyclic Phosphoramidate Prodrug of 2′-Deoxy-2′-Fluoro-2′- <i>C</i> -Methylguanosine for the Treatment of Dengue Virus Infection
Ratna Karuna, Fumiaki Yokokawa, Keshi Wang, Jin Zhang, Haoying Xu, Gang Wang, Mei Ding, Wai Ling Chan, Nahdiyah Abdul Ghafar, Andrea Leonardi, Cheah C. Seh, Peck Gee Seah, Wei Liu, Rao P. S. Srinivasa, Siew Pheng Lim, Suresh B. Lakshminarayana, Ellie Growcott, Sreehari Babu, Martijn Fenaux, Weidong Zhong, Feng Gu, Pei‐Yong Shi, Francesca Blasco, Yen‐Liang Chen
Abstract
Monophosphate prodrug analogs of 2′-deoxy-2′-fluoro-2′- C -methylguanosine have been reported as potent inhibitors of hepatitis C virus (HCV) RNA-dependent RNA polymerase. These prodrugs also display potent anti-dengue virus activities in cellular assays although their prodrug moieties were designed to produce high levels of triphosphate in the liver. Since peripheral blood mononuclear cells (PBMCs) are among the major targets of dengue virus, different prodrug moieties were designed to effectively deliver 2′-deoxy-2′-fluoro-2′- C -methylguanosine monophosphate prodrugs and their corresponding triphosphates into PBMCs after oral administration.