Structure-activity relationship of uridine-based nucleoside phosphoramidate prodrugs for inhibition of dengue virus RNA-dependent RNA polymerase

Gang Wang, Siew Pheng Lim, Yen Liang Chen, Jürg Hunziker, Ranga Rao, Feng Gu, Cheah Chen Seh, Nahdiyah Abdul Ghafar, Haoying Xu, Katherine Chan, Xiaodong Lin, Oliver L. Saunders, Martijn Fenaux, Weidong Zhong, Pei-Yong Shi, Fumiaki Yokokawa

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

To identify a potent and selective nucleoside inhibitor of dengue virus RNA-dependent RNA polymerase, a series of 2′- and/or 4′-ribose sugar modified uridine nucleoside phosphoramidate prodrugs and their corresponding triphosphates were synthesized and evaluated. Replacement of 2′-OH with 2′-F led to be a poor substrate for both dengue virus and human mitochondrial RNA polymerases. Instead of 2′-fluorination, the introduction of fluorine at the ribose 4′-position was found not to affect the inhibition of the dengue virus polymerase with a reduction in uptake by mitochondrial RNA polymerase. 2′-C-ethynyl-4′-F-uridine phosphoramidate prodrug displayed potent anti-dengue virus activity in the primary human peripheral blood mononuclear cell-based assay with no significant cytotoxicity in human hepatocellular liver carcinoma cell lines and no mitochondrial toxicity in the cell-based assay using human prostate cancer cell lines.

Original languageEnglish (US)
JournalBioorganic and Medicinal Chemistry Letters
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

RNA Replicase
Dengue Virus
Uridine
Prodrugs
Structure-Activity Relationship
Viruses
Nucleosides
Ribose
DNA-Directed RNA Polymerases
Assays
Cells
Cell Line
Fluorination
Fluorine
Halogenation
Cytotoxicity
Sugars
Liver
Toxicity
Hepatocellular Carcinoma

Keywords

  • Dengue virus
  • Mitochondrial RNA polymerase
  • Nucleoside
  • Phosphoramidate prodrug
  • RNA-dependent RNA polymerase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Structure-activity relationship of uridine-based nucleoside phosphoramidate prodrugs for inhibition of dengue virus RNA-dependent RNA polymerase. / Wang, Gang; Lim, Siew Pheng; Chen, Yen Liang; Hunziker, Jürg; Rao, Ranga; Gu, Feng; Seh, Cheah Chen; Ghafar, Nahdiyah Abdul; Xu, Haoying; Chan, Katherine; Lin, Xiaodong; Saunders, Oliver L.; Fenaux, Martijn; Zhong, Weidong; Shi, Pei-Yong; Yokokawa, Fumiaki.

In: Bioorganic and Medicinal Chemistry Letters, 01.01.2018.

Research output: Contribution to journalArticle

Wang, G, Lim, SP, Chen, YL, Hunziker, J, Rao, R, Gu, F, Seh, CC, Ghafar, NA, Xu, H, Chan, K, Lin, X, Saunders, OL, Fenaux, M, Zhong, W, Shi, P-Y & Yokokawa, F 2018, 'Structure-activity relationship of uridine-based nucleoside phosphoramidate prodrugs for inhibition of dengue virus RNA-dependent RNA polymerase', Bioorganic and Medicinal Chemistry Letters. https://doi.org/10.1016/j.bmcl.2018.04.069
Wang, Gang ; Lim, Siew Pheng ; Chen, Yen Liang ; Hunziker, Jürg ; Rao, Ranga ; Gu, Feng ; Seh, Cheah Chen ; Ghafar, Nahdiyah Abdul ; Xu, Haoying ; Chan, Katherine ; Lin, Xiaodong ; Saunders, Oliver L. ; Fenaux, Martijn ; Zhong, Weidong ; Shi, Pei-Yong ; Yokokawa, Fumiaki. / Structure-activity relationship of uridine-based nucleoside phosphoramidate prodrugs for inhibition of dengue virus RNA-dependent RNA polymerase. In: Bioorganic and Medicinal Chemistry Letters. 2018.
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