title: Resistance analysis and characterization of a thiazole analogue, BP008, as a potent hepatitis C virus NS5A inhibitor.
abstract: Hepatitis C virus (HCV) is a global health problem, affecting approximately 3% of the world's population. The standard treatment for HCV infection is often poorly tolerated and ineffective. Therefore, the development of novel or more effective treatment strategies to treat chronic HCV infection is urgently needed. In this report, BP008, a potent small-molecule inhibitor of HCV replication, was developed from a class of compounds with thiazol core structures by means of utilizing a cell-based HCV replicon system. The compound reduced the reporter expression of the HCV1b replicon with a 50% effective concentration (EC(50)) and selective index value of 4.1 ± 0.7 nM and >12,195, respectively. Sequencing analyses of several individual clones derived from BP008-resistant RNAs purified from cells harboring HCV1b replicon revealed that amino acid substitutions mainly within the N-terminal region (domain I) of NS5A were associated with decreased inhibitor susceptibility. Q24L, P58S, and Y93H are the key substitutions for resistance selection; F149L and V153M play the compensatory role in the replication and drug resistance processes. Moreover, BP008 displayed synergistic effects with alpha interferon (IFN-α), NS3 protease inhibitor, and NS5B polymerase inhibitor, as well as good oral bioavailability in SD rats and favorable exposure in rat liver. In summary, our results pointed to an effective small-molecule inhibitor, BP008, that potentially targets HCV NS5A. BP008 can be considered a part of a more effective therapeutic strategy for HCV in the future.
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan Town, Miaoli County 350, Taiwan.
authors: Hui-Mei
authors: HM
authors: Lin
authors: Jing-Chyi
authors: JC
authors: Wang
authors: Han-Shu
authors: HS
authors: Hu
authors: Pei-Shan
authors: PS
authors: Wu
authors: Chi-Chen
authors: CC
authors: Yang
authors: Chung-Pu
authors: CP
authors: Wu
authors: Szu-Yuan
authors: SY
authors: Pu
authors: Tsu-An
authors: TA
authors: Hsu
authors: Weir-Torn
authors: WT
authors: Jiaang
authors: Yu-Sheng
authors: YS
authors: Chao
authors: Jyh-Haur
authors: JH
authors: Chern
authors: Teng-Kuang
authors: TK
authors: Yeh
authors: Andrew
authors: A
authors: Yueh
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D024882:Drug Resistance, Viral / Q000187:drug effects*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D017930:Genes, Reporter; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D022781:Hepatocytes / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D008297:Male; D051381:Rats; D012093:Replicon; D013844:Thiazoles / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C573994:BP008; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase