Activation of peripheral blood mononuclear cells by dengue virus infection depotentiates balapiravir

Yen Liang Chen, Nahdiyah Abdul Ghafar, Ratna Karuna, Yilong Fu, Siew Pheng Lim, Wouter Schul, Feng Gu, Maxime Herve, Fumiaki Yokohama, Gang Wang, Daniela Cerny, Katja Fink, Francesca Blasco, Pei-Yong Shi

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

In a recent clinical trial, balapiravir, a prodrug of a cytidine analog (R1479), failed to achieve efficacy (reducing viremia after treatment) in dengue patients, although the plasma trough concentration of R1479 remained above the 50% effective concentration (EC50). Here, we report experimental evidence to explain the discrepancy between the in vitro and in vivo results and its implication for drug development. R1479 lost its potency by 125-fold when balapiravir was used to treat primary human peripheral blood mononuclear cells (PBMCs; one of the major cells targeted for viral replication) that were preinfected with dengue virus. The elevated EC50 was greater than the plasma trough concentration of R1479 observed in dengue patients treated with balapiravir and could possibly explain the efficacy failure. Mechanistically, dengue virus infection triggered PBMCs to generate cytokines, which decreased their efficiency of conversion of R1479 to its triphosphate form (the active antiviral ingredient), resulting in decreased antiviral potency. In contrast to the cytidine-based compound R1479, the potency of an adenosine-based inhibitor of dengue virus (NITD008) was much less affected. Taken together, our results demonstrate that viral infection in patients before treatment could significantly affect the conversion of the prodrug to its active form; such an effect should be calculated when estimating the dose efficacious for humans.

Original languageEnglish (US)
Pages (from-to)1740-1747
Number of pages8
JournalJournal of Virology
Volume88
Issue number3
DOIs
StatePublished - Feb 2014
Externally publishedYes

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balapiravir
4'-azidocytidine
Dengue virus
Dengue Virus
Virus Diseases
mononuclear leukocytes
cytidine
Blood Cells
dengue
infection
Cytidine
Dengue
viremia
Prodrugs
adenosine
virus replication
Antiviral Agents
clinical trials
cytokines
ingredients

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Activation of peripheral blood mononuclear cells by dengue virus infection depotentiates balapiravir. / Chen, Yen Liang; Ghafar, Nahdiyah Abdul; Karuna, Ratna; Fu, Yilong; Lim, Siew Pheng; Schul, Wouter; Gu, Feng; Herve, Maxime; Yokohama, Fumiaki; Wang, Gang; Cerny, Daniela; Fink, Katja; Blasco, Francesca; Shi, Pei-Yong.

In: Journal of Virology, Vol. 88, No. 3, 02.2014, p. 1740-1747.

Research output: Contribution to journalArticle

Chen, YL, Ghafar, NA, Karuna, R, Fu, Y, Lim, SP, Schul, W, Gu, F, Herve, M, Yokohama, F, Wang, G, Cerny, D, Fink, K, Blasco, F & Shi, P-Y 2014, 'Activation of peripheral blood mononuclear cells by dengue virus infection depotentiates balapiravir', Journal of Virology, vol. 88, no. 3, pp. 1740-1747. https://doi.org/10.1128/JVI.02841-13
Chen, Yen Liang ; Ghafar, Nahdiyah Abdul ; Karuna, Ratna ; Fu, Yilong ; Lim, Siew Pheng ; Schul, Wouter ; Gu, Feng ; Herve, Maxime ; Yokohama, Fumiaki ; Wang, Gang ; Cerny, Daniela ; Fink, Katja ; Blasco, Francesca ; Shi, Pei-Yong. / Activation of peripheral blood mononuclear cells by dengue virus infection depotentiates balapiravir. In: Journal of Virology. 2014 ; Vol. 88, No. 3. pp. 1740-1747.
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