Discovery of JNJ-1802, a First-in-Class Pan-Serotype Dengue Virus NS4B Inhibitor

  • J Med Chem. 2024 Mar 14;67(5):4063-4082. doi: 10.1021/acs.jmedchem.3c02336.
Bart Kesteleyn  1 ,  Jean-François Bonfanti  2 ,  Dorothée Bardiot  3 ,  Benoît De Boeck  1 ,  Olivia Goethals  4 ,  Suzanne J F Kaptein  5 ,  Bart Stoops  1 ,  Erwin Coesemans  1 ,  Jérôme Fortin  2 ,  Philippe Muller  2 ,  Frédéric Doublet  2 ,  Gunter Carlens  3 ,  Mohamed Koukni  3 ,  Wim Smets  3 ,  Pierre Raboisson  1 ,  Patrick Chaltin  3  6 ,  Kenny Simmen  1 ,  Marnix Van Loock  4 ,  Johan Neyts  5  7 ,  Arnaud Marchand  3 ,  Tim H M Jonckers  1
Affiliations
  • 1. Janssen Research & Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse 2340, Belgium.
  • 2. Janssen Infectious Diseases Discovery, Janssen-Cilag, Chaussée du Vexin, Val de Reuil 27106, France.
  • 3. CISTIM Leuven vzw, Bioincubator 2, Gaston Geenslaan 2, Leuven 3001, Belgium.
  • 4. Janssen Global Public Health R&D, Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse 2340, Belgium.
  • 5. KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, Leuven 3000, Belgium.
  • 6. Centre for Drug Design and Discovery (CD3), KU Leuven, Bioincubator 2, Gaston Geenslaan 2, Leuven 3000, Belgium.
  • 7. Global Virus Network (GVN), Baltimore, Maryland 21201, United States.
PMID: 38482827 DOI: 10.1021/acs.jmedchem.3c02336
Abstract

Dengue is a global public health threat, with about half of the world's population at risk of contracting this mosquito-borne viral disease. Climate change, urbanization, and global travel accelerate the spread of Dengue Virus (DENV) to new areas, including southern parts of Europe and the US. Currently, no dengue-specific small-molecule Antiviral for prophylaxis or treatment is available. Here, we report the discovery of JNJ-1802 as a potent, pan-serotype DENV inhibitor (EC50's ranging from 0.057 to 11 nM against the four DENV serotypes). The observed oral bioavailability of JNJ-1802 across preclinical species, its low clearance in human hepatocytes, the absence of major in vitro pharmacology safety alerts, and a dose-proportional increase in efficacy against DENV-2 Infection in mice were all supportive of its selection as a development candidate against dengue. JNJ-1802 is being progressed in clinical studies for the prevention or treatment of dengue.