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. 2021 Oct;598(7881):504-509.
doi: 10.1038/s41586-021-03990-6. Epub 2021 Oct 6.

A pan-serotype dengue virus inhibitor targeting the NS3-NS4B interaction

Suzanne J F Kaptein  1 , Olivia Goethals  2 , Dominik Kiemel  3 , Arnaud Marchand  4 , Bart Kesteleyn  5 , Jean-François Bonfanti  6   7 , Dorothée Bardiot  4 , Bart Stoops  5 , Tim H M Jonckers  5 , Kai Dallmeier  1 , Peggy Geluykens  5   8 , Kim Thys  5 , Marjolein Crabbe  5 , Laurent Chatel-Chaix  3   9 , Max Münster  3 , Gilles Querat  10 , Franck Touret  10 , Xavier de Lamballerie  10 , Pierre Raboisson  5   11 , Kenny Simmen  5 , Patrick Chaltin  4   12 , Ralf Bartenschlager  3   13 , Marnix Van Loock  14 , Johan Neyts  15   16
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Free article

A pan-serotype dengue virus inhibitor targeting the NS3-NS4B interaction

Suzanne J F Kaptein et al. Nature. 2021 Oct.
Free article

Erratum in

  • Publisher Correction: A pan-serotype dengue virus inhibitor targeting the NS3-NS4B interaction.
    Kaptein SJF, Goethals O, Kiemel D, Marchand A, Kesteleyn B, Bonfanti JF, Bardiot D, Stoops B, Jonckers THM, Dallmeier K, Geluykens P, Thys K, Crabbe M, Chatel-Chaix L, Münster M, Querat G, Touret F, de Lamballerie X, Raboisson P, Simmen K, Chaltin P, Bartenschlager R, Van Loock M, Neyts J. Kaptein SJF, et al. Nature. 2021 Nov;599(7883):E2. doi: 10.1038/s41586-021-04123-9. Nature. 2021. PMID: 34671169 No abstract available.

Abstract

Dengue virus causes approximately 96 million symptomatic infections annually, manifesting as dengue fever or occasionally as severe dengue1,2. There are no antiviral agents available to prevent or treat dengue. Here, we describe a highly potent dengue virus inhibitor (JNJ-A07) that exerts nanomolar to picomolar activity against a panel of 21 clinical isolates that represent the natural genetic diversity of known genotypes and serotypes. The molecule has a high barrier to resistance and prevents the formation of the viral replication complex by blocking the interaction between two viral proteins (NS3 and NS4B), thus revealing a previously undescribed mechanism of antiviral action. JNJ-A07 has a favourable pharmacokinetic profile that results in outstanding efficacy against dengue virus infection in mouse infection models. Delaying start of treatment until peak viraemia results in a rapid and significant reduction in viral load. An analogue is currently in further development.

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References

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