title: Using an Old Drug to Target a New Drug Site: Application of Disulfiram to Target the Zn-Site in HCV NS5A Protein.
abstract: In viral proteins, labile Zn-sites, where Zn(2+) is crucial for maintaining the native protein structure but the Zn-bound cysteines are reactive, are promising drug targets. Here, we aim to (i) identify labile Zn-sites in viral proteins using guidelines established from our previous work and (ii) assess if clinically safe Zn-ejecting agents could eject Zn(2+) from the predicted target site and thus inhibit viral replication. As proof-of-concept, we identified a labile Zn-site in the hepatitis C virus (HCV) NS5A protein and showed that the antialcoholism drug, disulfiram, could inhibit HCV replication to a similar extent as the clinically used antiviral agent, ribavirin. The discovery of a novel viral target and a new role for disulfiram in inhibiting HCV replication will enhance the therapeutic armamentarium against HCV. The strategy presented can also be applied to identify labile sites in other bacterial or viral proteins that can be targeted by disulfiram or other clinically safe Zn-ejectors.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica , Taipei 115, Taiwan.
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Lee
authors.affiliation: Institute of Molecular Biology, Academia Sinica , Taipei 115, Taiwan.
authors.forename: Yulander
authors.initials: Y
authors.lastname: Duh
authors.affiliation: Institute of Molecular Biology, Academia Sinica , Taipei 115, Taiwan.
authors.forename: Shih-Ting
authors.initials: ST
authors.lastname: Wang
authors.affiliation: Institute of Molecular Biology, Academia Sinica , Taipei 115, Taiwan.
authors.forename: Michael M C
authors.initials: MM
authors.lastname: Lai
authors.affiliation: Institute of Molecular Biology, Academia Sinica , Taipei 115, Taiwan.
authors.forename: Hanna S
authors.initials: HS
authors.lastname: Yuan
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica , Taipei 115, Taiwan.|Department of Chemistry, National Tsing Hua University , Hsinchu 300, Taiwan.
authors.forename: Carmay
authors.initials: C
authors.lastname: Lim
mesh_terms: D000427:Alcohol Deterrents / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D004221:Disulfiram / Q000494:pharmacology*; D006801:Humans; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D017967:Zinc Compounds / Q000037:antagonists & inhibitors / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000427:Alcohol Deterrents; D000998:Antiviral Agents; D004221:Disulfiram; D017361:Viral Nonstructural Proteins; D017967:Zinc Compounds; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase