TY - JOUR
T1 - Blocking NS3–NS4B interaction inhibits dengue virus in non-human primates
AU - Goethals, Olivia
AU - Kaptein, Suzanne J.F.
AU - Kesteleyn, Bart
AU - Bonfanti, Jean François
AU - Van Wesenbeeck, Liesbeth
AU - Bardiot, Dorothée
AU - Verschoor, Ernst J.
AU - Verstrepen, Babs E.
AU - Fagrouch, Zahra
AU - Putnak, J. Robert
AU - Kiemel, Dominik
AU - Ackaert, Oliver
AU - Straetemans, Roel
AU - Lachau-Durand, Sophie
AU - Geluykens, Peggy
AU - Crabbe, Marjolein
AU - Thys, Kim
AU - Stoops, Bart
AU - Lenz, Oliver
AU - Tambuyzer, Lotke
AU - De Meyer, Sandra
AU - Dallmeier, Kai
AU - McCracken, Michael K.
AU - Gromowski, Gregory D.
AU - Rutvisuttinunt, Wiriya
AU - Jarman, Richard G.
AU - Karasavvas, Nicos
AU - Touret, Franck
AU - Querat, Gilles
AU - de Lamballerie, Xavier
AU - Chatel-Chaix, Laurent
AU - Milligan, Gregg N.
AU - Beasley, David W.C.
AU - Bourne, Nigel
AU - Barrett, Alan D.T.
AU - Marchand, Arnaud
AU - Jonckers, Tim H.M.
AU - Raboisson, Pierre
AU - Simmen, Kenny
AU - Chaltin, Patrick
AU - Bartenschlager, Ralf
AU - Bogers, Willy M.
AU - Neyts, Johan
AU - Van Loock, Marnix
N1 - Funding Information:
We thank A. T. Henze for her scientific writing support at Janssen Pharmaceutica NV; K. Vercauteren, T. De Marez, G. Herrera-Taracena, N. Voge and R. Draghia Akli for reviewing the manuscript; E. Peeters, S. De Bruyn, N. Verheyen, C. Van Hove, E. Coesemans, B. De Boeck, A. Beckers, P. Gysemberg, T. Loomans and K. Allaerts at Janssen Pharmaceutica NV, E. Maas, R. Pholien, C. De Keyzer, C. Vanderheydt, L. Bervoets and the staff at the Rega animal facility at KU Leuven, and J. Fortin, F. Doublet and P. Muller at Janssen-Cilag for technical assistance; G. Kiemenyi Kayere at BPRC for technical assistance; and the staff of the BPRC Animal Science Department. This work was supported by a Seeding Drug Discovery Award from the Wellcome Trust (grant numbers 089328/Z/09 and 106327/Z/14) and received funding from the Flanders Agency Innovation & Entrepreneurship (VLAIO O&O grants IWT 150863 and HBC.2019.2906). Part of this research work was performed using the ‘Caps-It’ research infrastructure (project ZW13-02) that was financially supported by the Hercules Foundation (FWO) and Rega Foundation, KU Leuven. Studies conducted at the University of Texas Medical Branch were undertaken with US Federal funds from the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract no. HHSN272201700040I. The material presented here has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors, and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense or its components. In some figures, basic templates obtained from the Servier Medical Art library (https://smart.servier.com/) were used.
Funding Information:
We thank A. T. Henze for her scientific writing support at Janssen Pharmaceutica NV; K. Vercauteren, T. De Marez, G. Herrera-Taracena, N. Voge and R. Draghia Akli for reviewing the manuscript; E. Peeters, S. De Bruyn, N. Verheyen, C. Van Hove, E. Coesemans, B. De Boeck, A. Beckers, P. Gysemberg, T. Loomans and K. Allaerts at Janssen Pharmaceutica NV, E. Maas, R. Pholien, C. De Keyzer, C. Vanderheydt, L. Bervoets and the staff at the Rega animal facility at KU Leuven, and J. Fortin, F. Doublet and P. Muller at Janssen-Cilag for technical assistance; G. Kiemenyi Kayere at BPRC for technical assistance; and the staff of the BPRC Animal Science Department. This work was supported by a Seeding Drug Discovery Award from the Wellcome Trust (grant numbers 089328/Z/09 and 106327/Z/14) and received funding from the Flanders Agency Innovation & Entrepreneurship (VLAIO O&O grants IWT 150863 and HBC.2019.2906). Part of this research work was performed using the ‘Caps-It’ research infrastructure (project ZW13-02) that was financially supported by the Hercules Foundation (FWO) and Rega Foundation, KU Leuven. Studies conducted at the University of Texas Medical Branch were undertaken with US Federal funds from the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract no. HHSN272201700040I. The material presented here has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors, and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense or its components. In some figures, basic templates obtained from the Servier Medical Art library ( https://smart.servier.com/ ) were used.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/3/23
Y1 - 2023/3/23
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=85149948167&partnerID=8YFLogxK
U2 - 10.1038/s41586-023-05790-6
DO - 10.1038/s41586-023-05790-6
M3 - Article
C2 - 36922586
AN - SCOPUS:85149948167
SN - 0028-0836
VL - 615
SP - 678
EP - 686
JO - Nature
JF - Nature
IS - 7953
ER -