Inhibition of dengue virus by an ester prodrug of an adenosine analog

Yen Liang Chen, Zheng Yin, Suresh B. Lakshminarayana, Min Qing, Wouter Schul, Jeyaraj Duraiswamy, Ravinder Reddi Kondreddi, Anne Goh, Hao Ying Xu, Andy Yip, Boping Liu, Margaret Weaver, Veronique Dartois, Thomas H. Keller, Pei-Yong Shi

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Dengue virus (DENV) is the most prevalent mosquito-borne viral pathogen that infects humans. Neither a vaccine nor an antiviral therapy is currently available for DENV. Here, we report an adenosine nucleoside prodrug that potently inhibits DENV replication both in cell culture and in a DENV mouse model. NITD449 (2′-C-acetylene-7-deaza-7-carbamoyladenosine) was initially identified as a parental compound that inhibits all four serotypes of DENV with low cytotoxicity. However, in vivo pharmacokinetic studies indicated that NITD449 had a low level of exposure in plasma when dosed orally. To increase the oral bioavailability, we covalently linked isobutyric acids to the 3′- and 5′-hydroxyl groups of ribose via ester linkage to NITD449, leading to the prodrug NITD203 (3′,5′-O-diisobutyryl-2′-C-acetylene-7- deaza-7-carbamoyl-adenosin). Pharmacokinetic analysis showed that upon oral dosing of the prodrug, NITD203 was readily converted to NITD449, resulting in improved exposure of the parental compound in plasma in both mouse and rat. In DENV-infected AG129 mice, oral dosing of the prodrug at 25 mg/kg of body weight reduced peak viremia by 30-fold. Antiviral spectrum analysis showed that NITD203 inhibited various flaviviruses (DENV, yellow fever virus, and West Nile virus) and hepatitis C virus but not Chikungunya virus (an alphavirus). Mode-of-action analysis, using a luciferase-reporting replicon, indicated that NITD203 inhibited DENV RNA synthesis. Although NITD203 exhibited potent in vitro and in vivo efficacies, the compound could not reach a satisfactory no-observable-adverse-effect level (NOAEL) in a 2-week in vivo toxicity study. Nevertheless, our results demonstrate that a prodrug approach using a nucleoside analog could potentially be developed for flavivirus antiviral therapy.

Original languageEnglish (US)
Pages (from-to)3255-3261
Number of pages7
JournalAntimicrobial Agents and Chemotherapy
Volume54
Issue number8
DOIs
StatePublished - Aug 1 2010
Externally publishedYes

Fingerprint

Dengue Virus
Prodrugs
Adenosine
Esters
Antiviral Agents
Flavivirus
Acetylene
Nucleosides
Pharmacokinetics
Chikungunya virus
Isobutyrates
Yellow fever virus
Alphavirus
West Nile virus
Replicon
Ribose
Viremia
Virus Replication
Culicidae
Luciferases

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Chen, Y. L., Yin, Z., Lakshminarayana, S. B., Qing, M., Schul, W., Duraiswamy, J., ... Shi, P-Y. (2010). Inhibition of dengue virus by an ester prodrug of an adenosine analog. Antimicrobial Agents and Chemotherapy, 54(8), 3255-3261. https://doi.org/10.1128/AAC.00397-10

Inhibition of dengue virus by an ester prodrug of an adenosine analog. / Chen, Yen Liang; Yin, Zheng; Lakshminarayana, Suresh B.; Qing, Min; Schul, Wouter; Duraiswamy, Jeyaraj; Kondreddi, Ravinder Reddi; Goh, Anne; Xu, Hao Ying; Yip, Andy; Liu, Boping; Weaver, Margaret; Dartois, Veronique; Keller, Thomas H.; Shi, Pei-Yong.

In: Antimicrobial Agents and Chemotherapy, Vol. 54, No. 8, 01.08.2010, p. 3255-3261.

Research output: Contribution to journalArticle

Chen, YL, Yin, Z, Lakshminarayana, SB, Qing, M, Schul, W, Duraiswamy, J, Kondreddi, RR, Goh, A, Xu, HY, Yip, A, Liu, B, Weaver, M, Dartois, V, Keller, TH & Shi, P-Y 2010, 'Inhibition of dengue virus by an ester prodrug of an adenosine analog', Antimicrobial Agents and Chemotherapy, vol. 54, no. 8, pp. 3255-3261. https://doi.org/10.1128/AAC.00397-10
Chen YL, Yin Z, Lakshminarayana SB, Qing M, Schul W, Duraiswamy J et al. Inhibition of dengue virus by an ester prodrug of an adenosine analog. Antimicrobial Agents and Chemotherapy. 2010 Aug 1;54(8):3255-3261. https://doi.org/10.1128/AAC.00397-10
Chen, Yen Liang ; Yin, Zheng ; Lakshminarayana, Suresh B. ; Qing, Min ; Schul, Wouter ; Duraiswamy, Jeyaraj ; Kondreddi, Ravinder Reddi ; Goh, Anne ; Xu, Hao Ying ; Yip, Andy ; Liu, Boping ; Weaver, Margaret ; Dartois, Veronique ; Keller, Thomas H. ; Shi, Pei-Yong. / Inhibition of dengue virus by an ester prodrug of an adenosine analog. In: Antimicrobial Agents and Chemotherapy. 2010 ; Vol. 54, No. 8. pp. 3255-3261.
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