Format

Send to

Choose Destination
Antiviral Res. 2017 Nov;147:149-158. doi: 10.1016/j.antiviral.2017.10.011. Epub 2017 Oct 14.

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

Author information

1
Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: Ilane.hernandezm@gmail.com.
2
Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: pgeluyke@its.jnj.com.
3
Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: mclynhen@its.jnj.com.
4
Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: rstrijbo@its.jnj.com.
5
Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: ogoethal@its.jnj.com.
6
Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: smegens@its.jnj.com.
7
Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: nverheye@its.jnj.com.
8
Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: slast@its.jnj.com.
9
Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: dmcgowan@its.jnj.com.
10
Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: ecoesema@its.jnj.com.
11
Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: bdboeck@its.jnj.com.
12
Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: bstoops1@its.jnj.com.
13
Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: benoit.devogelaere@agilent.com.
14
Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: fpauwels@its.jnj.com.
15
Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: kvandyck@its.jnj.com.
16
Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: jberke@its.jnj.com.
17
Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: praboiss@its.jnj.com.
18
Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: ksimmen1@its.jnj.com.
19
Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: plory@its.jnj.com.
20
Janssen Pharmaceutica NV, Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium. Electronic address: mvloock@its.jnj.com.

Abstract

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.

KEYWORDS:

Antiviral compound; Dengue; HCV; NS4B; Non-structural protein 4B

PMID:
29037976
DOI:
10.1016/j.antiviral.2017.10.011
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center