A Cyclic Phosphoramidate Prodrug of 2=-Deoxy-2=-Fluoro-2=-C-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 Chen Seh, Peck Gee Seah, Wei Liu, Rao P.S. Srinivasa, Siew Pheng Lim, Suresh B. Lakshminarayana, Ellie Growcott, Sreehari Babu, Martijn Fenaux, Weidong ZhongFeng Gu, Pei Yong Shi, Francesca Blasco, Yen Liang Chen

Research output: Contribution to journalArticlepeer-review

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. We identified a cyclic phosphoramidate, prodrug 17, demonstrating well-balanced anti-dengue virus cellular activity and in vitro stability profiles. We further determined the PBMC concentration of active triphosphate needed to inhibit virus replication by 50% (TP50). Compound 17 was assessed in an AG129 mouse model and demonstrated 1.6- and 2.2-log viremia reductions at 100 and 300 mg/kg twice a day (BID), respectively. At 100 mg/kg BID, the terminal triphosphate concentration in PBMCs exceeded the TP50 value, demonstrating TP50 as the target exposure for efficacy. In dogs, oral administration of compound 17 resulted in high PBMC triphosphate levels, exceeding the TP50 at 10 mg/kg. Unfortunately, 2-week dog toxicity studies at 30, 100, and 300 mg/kg/day showed that “no observed adverse effect level” (NOAEL) could not be achieved due to pulmonary inflammation and hemorrhage. The preclinical safety results suspended further development of compound 17. Nevertheless, present work has proven the concept that an efficacious monophosphate nucleoside prodrug could be developed for the potential treatment of dengue virus infection.

Original languageEnglish (US)
Article numbere00654-20
JournalAntimicrobial agents and chemotherapy
Volume64
Issue number12
DOIs
StatePublished - Dec 2020
Externally publishedYes

Keywords

  • Cyclic phosphoramidate
  • Dengue
  • Monophosphate prodrug
  • Nucleoside triphosphate
  • Nucleotide analog
  • Polymerase inhibitor

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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