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

  • Nature. 2021 Oct;598(7881):504-509. doi: 10.1038/s41586-021-03990-6.
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
Affiliations
  • 1. Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
  • 2. Janssen Global Public Health, Janssen Pharmaceutica, Beerse, Belgium.
  • 3. Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
  • 4. Cistim Leuven, Leuven, Belgium.
  • 5. Janssen Research & Development, Janssen Pharmaceutica, Beerse, Belgium.
  • 6. Janssen Infectious Diseases Discovery, Janssen-Cilag, Val de Reuil, France.
  • 7. Galapagos, Romainville, France.
  • 8. Charles River Beerse, Discovery, Beerse, Belgium.
  • 9. Institut National de la Recherche Scientifique, Centre Armand-Frappier Santé Biotechnologie, Quebec, Quebec, Canada.
  • 10. Unité des Virus Émergents (UVE), Aix-Marseille Univ, IRD 190 Inserm 1207, IHU Méditerranée Infection, Marseille, France.
  • 11. Aligos, Leuven, Belgium.
  • 12. Centre for Drug Design and Discovery (CD3), KU Leuven, Leuven, Belgium.
  • 13. German Center for Infection Research, Heidelberg Partner Site, Heidelberg, Germany.
  • 14. Janssen Global Public Health, Janssen Pharmaceutica, Beerse, Belgium. [email protected].
  • 15. Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium. [email protected].
  • 16. Global Virus Network (GVN), Baltimore, MD, USA. [email protected].
PMID: 34616043 DOI: 10.1038/s41586-021-03990-6
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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