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

Olivia Goethals, Suzanne J. F. Kaptein, Bart Kesteleyn, Jean-François Bonfanti, Liesbeth Wesenbeeck, Dorothée Bardiot, Ernst J. Verschoor, Babs E. Verstrepen, Zahra Fagrouch, J. Robert Putnak, Dominik Kiemel, Oliver Ackaert, Roel Straetemans, Sophie Lachau-Durand, Peggy Geluykens, Marjolein Crabbe, Kim Thys, Bart Stoops, Oliver Lenz, Lotke Tambuyzer, Sandra Meyer, Kai Dallmeier, Michael K. McCracken, Gregory D. Gromowski, Wiriya Rutvisuttinunt, Richard G. Jarman, Nicos Karasavvas, Franck Touret, Gilles Querat, Xavier Lamballerie, Laurent Chatel-Chaix, Gregg N. Milligan, David W. C. Beasley, Nigel Bourne, Alan D. T. Barrett, Arnaud Marchand, Tim H. M. Jonckers, Pierre Raboisson, Kenny Simmen, Patrick Chaltin, Ralf Bartenschlager, Willy M. Bogers, Johan Neyts and Marnix Loock ()
Additional contact information
Olivia Goethals: Janssen Pharmaceutica NV
Suzanne J. F. Kaptein: KU Leuven
Bart Kesteleyn: Janssen Pharmaceutica NV
Jean-François Bonfanti: Janssen-Cilag
Liesbeth Wesenbeeck: Janssen Pharmaceutica NV
Dorothée Bardiot: Cistim Leuven vzw
Ernst J. Verschoor: Biomedical Primate Research Centre
Babs E. Verstrepen: Biomedical Primate Research Centre
Zahra Fagrouch: Biomedical Primate Research Centre
J. Robert Putnak: Walter Reed Army Institute of Research
Dominik Kiemel: Center for Integrative Infectious Diseases Research
Oliver Ackaert: Janssen Pharmaceutica NV
Roel Straetemans: Janssen Pharmaceutica NV
Sophie Lachau-Durand: Janssen Pharmaceutica NV
Peggy Geluykens: Janssen Pharmaceutica NV
Marjolein Crabbe: Janssen Pharmaceutica NV
Kim Thys: Janssen Pharmaceutica NV
Bart Stoops: Janssen Pharmaceutica NV
Oliver Lenz: Janssen Pharmaceutica NV
Lotke Tambuyzer: Janssen Pharmaceutica NV
Sandra Meyer: Janssen Pharmaceutica NV
Kai Dallmeier: KU Leuven
Michael K. McCracken: Walter Reed Army Institute of Research
Gregory D. Gromowski: Walter Reed Army Institute of Research
Wiriya Rutvisuttinunt: Walter Reed Army Institute of Research
Richard G. Jarman: Walter Reed Army Institute of Research
Nicos Karasavvas: Walter Reed Army Institute of Research
Franck Touret: Aix-Marseille Université-IRD 190-Inserm 1207
Gilles Querat: Aix-Marseille Université-IRD 190-Inserm 1207
Xavier Lamballerie: Aix-Marseille Université-IRD 190-Inserm 1207
Laurent Chatel-Chaix: Center for Integrative Infectious Diseases Research
Gregg N. Milligan: The University of Texas Medical Branch Health
David W. C. Beasley: The University of Texas Medical Branch Health
Nigel Bourne: The University of Texas Medical Branch Health
Alan D. T. Barrett: The University of Texas Medical Branch Health
Arnaud Marchand: Cistim Leuven vzw
Tim H. M. Jonckers: Janssen Pharmaceutica NV
Pierre Raboisson: Janssen Pharmaceutica NV
Kenny Simmen: Johnson & Johnson Innovation
Patrick Chaltin: Cistim Leuven vzw
Ralf Bartenschlager: Center for Integrative Infectious Diseases Research
Willy M. Bogers: Biomedical Primate Research Centre
Johan Neyts: KU Leuven
Marnix Loock: Janssen Pharmaceutica NV

Nature, 2023, vol. 615, issue 7953, 678-686

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-05790-6

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