Journal Article

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

Jonckers, Tim H M, Straetemans, Roel, Gromowski, Gregory D, Verschoor, Ernst J, Geluykens, Peggy, Bourne, Nigel, Simmen, Kenny, Chaltin, Patrick, Barrett, Alan D T, Kaptein, Suzanne J F, Crabbe, Marjolein, Neyts, Johan, Bartenschlager, Ralf, van Wesenbeeck, Liesbeth, Lachau-Durand, Sophie, Stoops, Bart, Fagrouch, Zahra, Goethals, Olivia, Mccracken, Michael K, Tambuyzer, Lotke, Lenz, Oliver, Touret, Franck, de Meyer, Sandra, Kesteleyn, Bart, Verstrepen, Babs E, Innovation et Développement dans l'Agriculture et l'Alimentation (UMR Innovation) ; Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Montpellier ; Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Bogers, Willy M, Jarman, Richard G, Karasavvas, Nicos, Beasley, David

2023

Overview

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. © 2023. The Author(s).

• Publisher: Nature Publishing Group,CCSD,Nature Publishing Group UK
• Subject: 13/1 / 13/106 / 13/109 / 13/51 / 14/63 / 38/109 / 38/44 / 38/90 / 631/154 / 64/60 / 692/699 / 82/29 / Animals / Antiviral activity / Antiviral agents / Antiviral Agents - adverse effects / Antiviral Agents - pharmacology / Antiviral Agents - therapeutic use / Antiviral drugs / Clinical Trials, Phase I as Topic / Dengue - drug therapy / Dengue - prevention & control / Dengue - virology / Dengue fever / Dengue Virus - classification / Dengue Virus - drug effects / Disease prevention / Dose-Response Relationship, Drug / Drug dosages / Drug Resistance, Viral / Health risks / Humanities and Social Sciences / Humans / In Vitro Techniques / Infections / Inhibitors / Laboratories / Life Sciences / Mice / Molecular Targeted Therapy / Mosquitoes / multidisciplinary / Mutation / Population / Primates / Primates - virology / Protein Binding - drug effects / Proteins / Science / Science (multidisciplinary) / Serotypes / Structural proteins / Vaccines / Vector-borne diseases / Viral infections / Viral Nonstructural Proteins - antagonists & inhibitors / Viral Nonstructural Proteins - metabolism / Virus Replication / Viruses / West Nile virus