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

Olivia Goethals; Suzanne J.F. Kaptein; Bart Kesteleyn; Jean François Bonfanti; Liesbeth Van 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 De Meyer; Kai Dallmeier; Michael K. McCracken; Gregory D. Gromowski; Wiriya Rutvisuttinunt; Richard G. Jarman; Nicos Karasavvas; Franck Touret; Gilles Querat; Xavier de 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; Marnix Van Loock

doi:10.1038/s41586-023-05790-6

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

Olivia Goethals, Suzanne J.F. Kaptein, Bart Kesteleyn, Jean François Bonfanti, Liesbeth Van 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 TambuyzerSandra De Meyer, Kai Dallmeier, Michael K. McCracken, Gregory D. Gromowski, Wiriya Rutvisuttinunt, Richard G. Jarman, Nicos Karasavvas, Franck Touret, Gilles Querat, Xavier de 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, Marnix Van Loock

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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.

Original language	English (US)
Pages (from-to)	678-686
Number of pages	9
Journal	Nature
Volume	615
Issue number	7953
DOIs	https://doi.org/10.1038/s41586-023-05790-6
State	Published - Mar 23 2023

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Goethals, O., Kaptein, S. J. F., Kesteleyn, B., Bonfanti, J. F., Van Wesenbeeck, L., Bardiot, D., Verschoor, E. J., Verstrepen, B. E., Fagrouch, Z., Putnak, J. R., Kiemel, D., Ackaert, O., Straetemans, R., Lachau-Durand, S., Geluykens, P., Crabbe, M., Thys, K., Stoops, B., Lenz, O., ... Van Loock, M. (2023). Blocking NS3–NS4B interaction inhibits dengue virus in non-human primates. Nature, 615(7953), 678-686. https://doi.org/10.1038/s41586-023-05790-6

Goethals, O, Kaptein, SJF, Kesteleyn, B, Bonfanti, JF, Van Wesenbeeck, L, Bardiot, D, Verschoor, EJ, Verstrepen, BE, Fagrouch, Z, Putnak, JR, Kiemel, D, Ackaert, O, Straetemans, R, Lachau-Durand, S, Geluykens, P, Crabbe, M, Thys, K, Stoops, B, Lenz, O, Tambuyzer, L, De Meyer, S, Dallmeier, K, McCracken, MK, Gromowski, GD, Rutvisuttinunt, W, Jarman, RG, Karasavvas, N, Touret, F, Querat, G, de Lamballerie, X, Chatel-Chaix, L, Milligan, GN, Beasley, DWC , Bourne, N , Barrett, ADT, Marchand, A, Jonckers, THM, Raboisson, P, Simmen, K, Chaltin, P, Bartenschlager, R, Bogers, WM, Neyts, J & Van Loock, M 2023, 'Blocking NS3–NS4B interaction inhibits dengue virus in non-human primates', Nature, vol. 615, no. 7953, pp. 678-686. https://doi.org/10.1038/s41586-023-05790-6

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title = "Blocking NS3–NS4B interaction inhibits dengue virus in non-human primates",

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.",

author = "Olivia Goethals and Kaptein, {Suzanne J.F.} and Bart Kesteleyn and Bonfanti, {Jean Fran{\c c}ois} and {Van Wesenbeeck}, Liesbeth and Doroth{\'e}e Bardiot and Verschoor, {Ernst J.} and Verstrepen, {Babs E.} and Zahra Fagrouch and Putnak, {J. Robert} and Dominik Kiemel and Oliver Ackaert and Roel Straetemans and Sophie Lachau-Durand and Peggy Geluykens and Marjolein Crabbe and Kim Thys and Bart Stoops and Oliver Lenz and Lotke Tambuyzer and {De Meyer}, Sandra and Kai Dallmeier and McCracken, {Michael K.} and Gromowski, {Gregory D.} and Wiriya Rutvisuttinunt and Jarman, {Richard G.} and Nicos Karasavvas and Franck Touret and Gilles Querat and {de Lamballerie}, Xavier and Laurent Chatel-Chaix and Milligan, {Gregg N.} and Beasley, {David W.C.} and Nigel Bourne and Barrett, {Alan D.T.} and Arnaud Marchand and Jonckers, {Tim H.M.} and Pierre Raboisson and Kenny Simmen and Patrick Chaltin and Ralf Bartenschlager and Bogers, {Willy M.} and Johan Neyts and {Van Loock}, Marnix",

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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

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

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