Characterization of a dengue NS4B inhibitor originating from an HCV small molecule library

• Published in: Antiviral research Vol. 147; pp. 149 - 158
• Main Authors: Hernandez-Morales, Ilane, Geluykens, Peggy, Clynhens, Marleen, Strijbos, Rudy, Goethals, Olivia, Megens, Sarah, Verheyen, Nick, Last, Stefaan, McGowan, David, Coesemans, Erwin, De Boeck, Benoît, Stoops, Bart, Devogelaere, Benoit, Pauwels, Frederik, Vandyck, Koen, Berke, Jan Martin, Raboisson, Pierre, Simmen, Kenneth, Lory, Pedro, Van Loock, Marnix
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2017
• Subjects: Animals; Antiviral Agents - chemistry; Antiviral Agents - pharmacokinetics; Antiviral Agents - pharmacology; Antiviral Agents - toxicity; Antiviral compound; Cell Line, Tumor; Cercopithecus aethiops; Dengue; Dengue Virus - drug effects; Dengue Virus - genetics; Dengue Virus - physiology; Drug Discovery; Drug Resistance, Viral - drug effects; Drug Resistance, Viral - genetics; HCV; Hepacivirus - genetics; Humans; Mutation; Non-structural protein 4B; NS4B; Replicon - drug effects; RNA, Viral - genetics; Sequence Analysis, RNA; Small Molecule Libraries; Vero Cells; Viral Nonstructural Proteins - genetics; Virus Replication - drug effects; Dengue; NS4B; Antiviral compound; HCV; Non-structural protein 4B; 2′CMC; RLuc
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2017.10.011

Dengue is the most important mosquito-transmitted viral disease and a major global health concern. Over the last decade, dengue virus (DENV) drug discovery and development has intensified, however, this has not resulted in approved DENV-specific antiviral treatments yet. DENV and hepatitis C virus (HCV) belong to the same Flaviviridae family and, in contrast to DENV, antiviral treatments for HCV have been licensed. Therefore, applying the knowledge gained on anti-HCV drugs may foster the discovery and development of dengue antiviral drugs. Here, we screened a library of compounds with established anti-HCV activity in a DENV-2 sub-genomic replicon inhibition assay and selected compounds with single-digit micromolar activity. These compounds were advanced into a hit-to-lead medicinal chemistry program resulting in lead compound JNJ-1A, which inhibited the DENV-2 sub-genomic replicon at 0.7 μM, in the absence of cytotoxicity. In addition, JNJ-1A showed equipotent antiviral activity against DENV serotypes 1, 2, and 4. In vitro resistance selection experiments with JNJ-1A induced mutation T108I in non-structural protein 4B (NS4B), pointing towards a mechanism of action linked to this protein. Collectively, we described the discovery and characterization of a novel DENV inhibitor potentially targeting NS4B. •Compound JNJ-1A showed equipotent antiviral activity against DENV-1, 2, and 4.•Compound JNJ-1A inhibited DENV replication by targeting NS4B.•Within NS4B, T108I was identified as a resistance-associated mutation.