التفاصيل البيبلوغرافية
| العنوان: |
Characterization of a dengue NS4B inhibitor originating from an HCV small molecule library. |
| المؤلفون: |
Hernandez-Morales, Ilane1 Ilane.hernandezm@gmail.com, Geluykens, Peggy1 pgeluyke@its.jnj.com, Clynhens, Marleen1 mclynhen@its.jnj.com, Strijbos, Rudy1 rstrijbo@its.jnj.com, Goethals, Olivia1 ogoethal@its.jnj.com, Megens, Sarah1 smegens@its.jnj.com, Verheyen, Nick1 nverheye@its.jnj.com, Last, Stefaan1 slast@its.jnj.com, McGowan, David1 dmcgowan@its.jnj.com, Coesemans, Erwin1 ecoesema@its.jnj.com, De Boeck, Benoît1 bdboeck@its.jnj.com, Stoops, Bart1 bstoops1@its.jnj.com, Devogelaere, Benoit1 benoit.devogelaere@agilent.com, Pauwels, Frederik1 fpauwels@its.jnj.com, Vandyck, Koen1 kvandyck@its.jnj.com, Berke, Jan Martin1 jberke@its.jnj.com, Raboisson, Pierre1 praboiss@its.jnj.com, Simmen, Kenneth1 ksimmen1@its.jnj.com, Lory, Pedro1 plory@its.jnj.com, Van Loock, Marnix1 mvloock@its.jnj.com |
| المصدر: |
Antiviral Research. Nov2017, Vol. 147, p149-158. 10p. |
| مصطلحات موضوعية: |
*DENGUE, *THERAPEUTICS, *HEPATITIS C virus, *MOSQUITO vectors, *DRUG development, *ANTIVIRAL agents |
| مستخلص: |
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. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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