Identification of Compound-B, a novel anti-dengue virus agent targeting the non-structural protein 4A

Haruaki Nobori; Shinsuke Toba; Ryu Yoshida; William W Hall; Yasuko Orba; Hirofumi Sawa; Akihiko Sato

doi:10.1016/j.antiviral.2018.05.003

Identification of Compound-B, a novel anti-dengue virus agent targeting the non-structural protein 4A

Antiviral Res. 2018 Jul:155:60-66. doi: 10.1016/j.antiviral.2018.05.003. Epub 2018 May 11.

Authors

Haruaki Nobori¹, Shinsuke Toba¹, Ryu Yoshida², William W Hall³, Yasuko Orba⁴, Hirofumi Sawa⁵, Akihiko Sato⁶

Affiliations

¹ Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan; Division of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan.
² Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan.
³ Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan; Center for Research in Infectious Diseases, University College of Dublin, Dublin, Ireland; Global Virus Network, Baltimore, MD, USA.
⁴ Division of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan.
⁵ Division of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan; Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan; Global Virus Network, Baltimore, MD, USA.
⁶ Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan; Division of Molecular Pathobiology, Research Center for Zoonosis Control, Hokkaido University, Sapporo, Japan. Electronic address: akihiko.sato@shionogi.co.jp.

PMID: 29758236
DOI: 10.1016/j.antiviral.2018.05.003

Abstract

Dengue virus (DENV) is the causative agent of dengue fever and dengue hemorrhagic fever/dengue shock syndrome. At present, no antiviral drugs are available for treatment DENV infections. In this study, a screening system based on a DENV-infected cell-based assay identified a novel anti-DENV agent with a benzimidazole skeleton, named Compound-B, which demonstrated antiviral activity specific to four DENV serotypes (EC₅₀: 1.32-4.12 μM). Analysis of a single amino acid substitution of Compound-B-resistant DENV2 revealed that mutation C87S in the non-structural protein 4A (NS4A) contributes to resistance to Compound-B.

Keywords: Benzimidazole skeleton; Cell-based assay; Compound resistant virus; Dengue virus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Amino Acid Substitution
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Benzimidazoles / chemistry
Benzimidazoles / pharmacology*
Dengue Virus / drug effects*
Dengue Virus / genetics
Drug Resistance, Viral / genetics
Humans
Mutation
Serogroup
Small Molecule Libraries
Viral Nonstructural Proteins / genetics
Virus Replication / drug effects*

Substances

Antiviral Agents
Benzimidazoles
NS4A protein, Dengue virus
Small Molecule Libraries
Viral Nonstructural Proteins
benzimidazole