2. Academic Validation
  3. Blocking NS3-NS4B interaction inhibits dengue virus in non-human primates

Blocking NS3-NS4B interaction inhibits dengue virus in non-human primates

  • Nature. 2023 Mar;615(7953):678-686. doi: 10.1038/s41586-023-05790-6.
Olivia Goethals 1,  Suzanne J F Kaptein 2,  Bart Kesteleyn 3,  Jean-François Bonfanti 4 5,  Liesbeth Van Wesenbeeck 3,  Dorothée Bardiot 6,  Ernst J Verschoor 7,  Babs E Verstrepen 7,  Zahra Fagrouch 7,  J Robert Putnak 8,  Dominik Kiemel 9,  Oliver Ackaert 10,  Roel Straetemans 11,  Sophie Lachau-Durand 3,  Peggy Geluykens 3 12,  Marjolein Crabbe 11,  Kim Thys 3,  Bart Stoops 3,  Oliver Lenz 3,  Lotke Tambuyzer 3,  Sandra De Meyer 3,  Kai Dallmeier 2,  Michael K McCracken 8,  Gregory D Gromowski 8,  Wiriya Rutvisuttinunt 8,  Richard G Jarman 8,  Nicos Karasavvas 8,  Franck Touret 13,  Gilles Querat 13,  Xavier de Lamballerie 13,  Laurent Chatel-Chaix 9 14,  Gregg N Milligan 15,  David W C Beasley 15,  Nigel Bourne 15,  Alan D T Barrett 15,  Arnaud Marchand 6,  Tim H M Jonckers 3,  Pierre Raboisson 3 16,  Kenny Simmen 17,  Patrick Chaltin 6 18,  Ralf Bartenschlager 9 19,  Willy M Bogers 7,  Johan Neyts 2 20,  Marnix Van Loock 21
Affiliations

Affiliations

  • 1 Janssen Global Public Health, Janssen Pharmaceutica NV, Beerse, Belgium.
  • 2 Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven, Leuven, Belgium.
  • 3 Janssen Research & Development, Janssen Pharmaceutica NV, Beerse, Belgium.
  • 4 Janssen Infectious Diseases Discovery, Janssen-Cilag, Val de Reuil, France.
  • 5 Galapagos, Romainville, France.
  • 6 Cistim Leuven vzw, Leuven, Belgium.
  • 7 Department of Virology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
  • 8 Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
  • 9 Heidelberg University, Medical Faculty Heidelberg, Department of Infectious Diseases, Molecular Virology, Center for Integrative Infectious Diseases Research, Heidelberg, Germany.
  • 10 Janssen Clinical Pharmacology and Pharmacometrics, Janssen Pharmaceutica NV, Beerse, Belgium.
  • 11 Statistics and Decision Sciences, Janssen Pharmaceutica NV, Beerse, Belgium.
  • 12 Discovery, Charles River Beerse, Beerse, Belgium.
  • 13 Unité des Virus Émergents, Aix-Marseille Université-IRD 190-Inserm 1207, Marseille, France.
  • 14 Centre Armand-Frappier Santé Biotechnologie, Institut National de la Recherche Scientifique, Laval, Quebec, Canada.
  • 15 Sealy Institute for Vaccine Sciences, The University of Texas Medical Branch Health, Galveston, TX, USA.
  • 16 Galapagos NV, Mechelen, Belgium.
  • 17 Johnson & Johnson Innovation, London, UK.
  • 18 Centre for Drug Design and Discovery (CD3), KU Leuven, Leuven, Belgium.
  • 19 German Centre for Infection Research, Heidelberg Partner Site, Heidelberg, Germany.
  • 20 Global Virus Network (GVN), Baltimore, MD, USA.
  • 21 Janssen Global Public Health, Janssen Pharmaceutica NV, Beerse, Belgium. mvloock@its.jnj.com.
PMID: 36922586 DOI: 10.1038/s41586-023-05790-6
Abstract

Dengue is a major health threat and the number of symptomatic infections caused by the four dengue serotypes is estimated to be 96 million1 with annually around 10,000 deaths2. However, no Antiviral drugs are available for the treatment or prophylaxis of dengue. We recently described the interaction between non-structural proteins NS3 and NS4B as a promising target for the development of pan-serotype dengue virus (DENV) inhibitors3. Here we present JNJ-1802-a highly potent DENV inhibitor that blocks the NS3-NS4B interaction within the viral replication complex. JNJ-1802 exerts picomolar to low nanomolar in vitro Antiviral activity, a high barrier to resistance and potent in vivo efficacy in mice against Infection with any of the four DENV serotypes. Finally, we demonstrate that the small-molecule inhibitor JNJ-1802 is highly effective against viral Infection with DENV-1 or DENV-2 in non-human primates. JNJ-1802 has successfully completed a phase I first-in-human clinical study in healthy volunteers and was found to be safe and well tolerated4. These findings support the further clinical development of JNJ-1802, a first-in-class Antiviral agent against dengue, which is now progressing in clinical studies for the prevention and treatment of dengue.

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