2. Academic Validation
  3. Structure-activity relationship of uridine-based nucleoside phosphoramidate prodrugs for inhibition of dengue virus RNA-dependent RNA polymerase

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

  • Bioorg Med Chem Lett. 2018 Jul 15;28(13):2324-2327. doi: 10.1016/j.bmcl.2018.04.069.
Gang Wang 1,  Siew Pheng Lim 1,  Yen-Liang Chen 2,  Jürg Hunziker 3,  Ranga Rao 1,  Feng Gu 2,  Cheah Chen Seh 1,  Nahdiyah Abdul Ghafar 1,  Haoying Xu 1,  Katherine Chan 2,  Xiaodong Lin 4,  Oliver L Saunders 4,  Martijn Fenaux 4,  Weidong Zhong 4,  Pei-Yong Shi 5,  Fumiaki Yokokawa 6
Affiliations

Affiliations

  • 1 Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos Singapore 138670, Singapore.
  • 2 Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos Singapore 138670, Singapore; Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
  • 3 Novartis Institutes for BioMedical Research, Forum 1 Novartis Campus, CH-4056 Basel, Switzerland.
  • 4 Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
  • 5 Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos Singapore 138670, Singapore; Department of Biochemistry & Molecular Biology, Department of Pharmacology & Toxicology, Sealy Center for Structural Biology & Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, United States.
  • 6 Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos Singapore 138670, Singapore; Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States. Electronic address: fumiaki.yokokawa@novartis.com.
PMID: 29801997 DOI: 10.1016/j.bmcl.2018.04.069
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.

Keywords

Dengue virus; Mitochondrial RNA polymerase; Nucleoside; Phosphoramidate prodrug; RNA-dependent RNA polymerase.

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