title: A hepatitis C virus NS4B inhibitor suppresses viral genome replication by disrupting NS4B's dimerization/multimerization as well as its interaction with NS5A.
abstract: Chronic hepatitis C virus (HCV) infection is responsible for severe liver diseases including liver cirrhosis and hepatocellular carcinoma. An HCV non-structural protein 4B (NS4B) plays an essential role in viral RNA genome replication by building multi-vesicular structures around endoplasmic reticulum membranes. Especially, the second amphipathic helix of NS4B (NS4B-AH2) was shown to be essential for this process. By screening compounds against a membrane-aggregating activity of NS4B-AH2, several anti-HCV replication small molecules targeting NS4B-AH2 were discovered. However, little is known about detailed molecular mechanism of action for these NS4B-AH2 inhibitors. In this report, we provide evidences that NS4B-AH2 is required for NS4B's dimerization/multimerization, its proper subcellular localization, as well as its interaction with NS5A. More importantly, one of NS4B-AH2 inhibitors called "anguizole" was found to be able to disrupt all of these NS4B-AH2-mediated biological functions of NS4B. This newly elucidated mechanism of action will enable us not only to better understand a central role of NS4B-AH2 in HCV life cycle but also to develop a more safe and effective new class of NS4B-AH2 inhibitors of HCV replication in the future.
authors.affiliation: College of Pharmacy, Dongguk University-Seoul, Goyang, 410-050, South Korea.
authors.forename: Moonju
authors.initials: M
authors.lastname: Choi
authors.forename: Sungjin
authors.initials: S
authors.lastname: Lee
authors.forename: Taekyu
authors.initials: T
authors.lastname: Choi
authors.forename: Choongho
authors.initials: C
authors.lastname: Lee
mesh_terms: D019281:Dimerization; D016679:Genome, Viral; D016174:Hepacivirus / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006526:Hepatitis C / Q000821:virology*; D006801:Humans; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication; D012324:RNA-Dependent RNA Polymerase
chemical_list: D017361:Viral Nonstructural Proteins; C080107:NS4B protein, flavivirus; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase