PMID- 29037976 OWN - NLM STAT- MEDLINE DCOM- 20181211 LR - 20191210 IS - 1872-9096 (Electronic) IS - 0166-3542 (Linking) VI - 147 DP - 2017 Nov TI - Characterization of a dengue NS4B inhibitor originating from an HCV small molecule library. PG - 149-158 LID - S0166-3542(17)30165-1 [pii] LID - 10.1016/j.antiviral.2017.10.011 [doi] AB - 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 muM, 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. CI - Copyright (c) 2017 Elsevier B.V. All rights reserved. FAU - Hernandez-Morales, Ilane AU - Hernandez-Morales I AD - Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: Ilane.hernandezm@gmail.com. FAU - Geluykens, Peggy AU - Geluykens P AD - Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: pgeluyke@its.jnj.com. FAU - Clynhens, Marleen AU - Clynhens M AD - Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: mclynhen@its.jnj.com. FAU - Strijbos, Rudy AU - Strijbos R AD - Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: rstrijbo@its.jnj.com. FAU - Goethals, Olivia AU - Goethals O AD - Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: ogoethal@its.jnj.com. FAU - Megens, Sarah AU - Megens S AD - Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: smegens@its.jnj.com. FAU - Verheyen, Nick AU - Verheyen N AD - Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: nverheye@its.jnj.com. FAU - Last, Stefaan AU - Last S AD - Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: slast@its.jnj.com. FAU - McGowan, David AU - McGowan D AD - Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: dmcgowan@its.jnj.com. FAU - Coesemans, Erwin AU - Coesemans E AD - Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: ecoesema@its.jnj.com. FAU - De Boeck, Benoit AU - De Boeck B AD - Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: bdboeck@its.jnj.com. FAU - Stoops, Bart AU - Stoops B AD - Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: bstoops1@its.jnj.com. FAU - Devogelaere, Benoit AU - Devogelaere B AD - Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: benoit.devogelaere@agilent.com. FAU - Pauwels, Frederik AU - Pauwels F AD - Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: fpauwels@its.jnj.com. FAU - Vandyck, Koen AU - Vandyck K AD - Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: kvandyck@its.jnj.com. FAU - Berke, Jan Martin AU - Berke JM AD - Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: jberke@its.jnj.com. FAU - Raboisson, Pierre AU - Raboisson P AD - Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: praboiss@its.jnj.com. FAU - Simmen, Kenneth AU - Simmen K AD - Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: ksimmen1@its.jnj.com. FAU - Lory, Pedro AU - Lory P AD - Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: plory@its.jnj.com. FAU - Van Loock, Marnix AU - Van Loock M AD - Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: mvloock@its.jnj.com. LA - eng PT - Journal Article DEP - 20171014 PL - Netherlands TA - Antiviral Res JT - Antiviral research JID - 8109699 RN - 0 (Antiviral Agents) RN - 0 (RNA, Viral) RN - 0 (Small Molecule Libraries) RN - 0 (Viral Nonstructural Proteins) SB - IM MH - Animals MH - Antiviral Agents/chemistry/pharmacokinetics/*pharmacology/toxicity MH - Cell Line, Tumor MH - Chlorocebus aethiops MH - Dengue MH - Dengue Virus/*drug effects/genetics/physiology MH - Drug Discovery MH - Drug Resistance, Viral/drug effects/*genetics MH - Hepacivirus/genetics MH - Humans MH - Mutation MH - RNA, Viral/genetics MH - Replicon/drug effects MH - Sequence Analysis, RNA MH - Small Molecule Libraries MH - Vero Cells MH - Viral Nonstructural Proteins/*genetics MH - Virus Replication/*drug effects OTO - NOTNLM OT - Antiviral compound OT - Dengue OT - HCV OT - NS4B OT - Non-structural protein 4B EDAT- 2017/10/19 06:00 MHDA- 2018/12/12 06:00 CRDT- 2017/10/18 06:00 PHST- 2017/04/07 00:00 [received] PHST- 2017/10/08 00:00 [revised] PHST- 2017/10/12 00:00 [accepted] PHST- 2017/10/19 06:00 [pubmed] PHST- 2018/12/12 06:00 [medline] PHST- 2017/10/18 06:00 [entrez] AID - S0166-3542(17)30165-1 [pii] AID - 10.1016/j.antiviral.2017.10.011 [doi] PST - ppublish SO - Antiviral Res. 2017 Nov;147:149-158. doi: 10.1016/j.antiviral.2017.10.011. Epub 2017 Oct 14.