title: Cholesterol sulfate as a potential inhibitor of hepatitis C virus NS3 helicase.
abstract: Hepatitis C virus nonstructural protein 3 (NS3) helicase is a promising target for developing new therapeutics. In this study, we identified cholesterol sulfate (CS) as a novel NS3 helicase inhibitor (IC50 = 1.7 ± 0.2 µM with a Hill coefficient of 3.9) by screening the extracts from marine organisms. The lack of the sulfate group, sterol structure or alkyl side chain of CS diminished the inhibition, suggesting that an anion binding and hydrophobic region in NS3 may be a target site of CS. It was further found that CS partly inhibits NS3-RNA binding activity, but exerted no or less inhibition against ATPase and serine protease activities. Moreover, we demonstrated that CS probably does not bind to RNA. Our findings suggest that CS may inhibit NS3 helicase not by abolishing the other NS3 activities but by inducing conformational changes via interaction with possible allosteric sites of NS3.
authors: Department of Life Science and Medical Bioscience, Waseda University , Shinjuku-ku, Tokyo , Japan .
authors: Atsushi
authors: A
authors: Furuta
authors: Kazi Abdus
authors: KA
authors: Salam
authors: Nobuyoshi
authors: N
authors: Akimitsu
authors: Junichi
authors: J
authors: Tanaka
authors: Hidenori
authors: H
authors: Tani
authors: Atsuya
authors: A
authors: Yamashita
authors: Kohji
authors: K
authors: Moriishi
authors: Masamichi
authors: M
authors: Nakakoshi
authors: Masayoshi
authors: M
authors: Tsubuki
authors: Yuji
authors: Y
authors: Sekiguchi
authors: Satoshi
authors: S
authors: Tsuneda
authors: Naohiro
authors: N
authors: Noda
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000998:Antiviral Agents / Q000302:isolation & purification / Q000494:pharmacology*; D059001:Aquatic Organisms / Q000737:chemistry; D002788:Cholesterol Esters / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D015394:Molecular Structure; D011485:Protein Binding; D020365:RNA Helicases / Q000037:antagonists & inhibitors*; D057057:Serine Proteases / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000251:Adenosine Triphosphatases; D000998:Antiviral Agents; D002788:Cholesterol Esters; D020365:RNA Helicases; D057057:Serine Proteases; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C007045:cholesteryl sulfate