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http://ir.nhri.org.tw/handle/3990099045/6050
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| Title: | Resistance analysis and characterization of a thiazole analogue, BP008, as a potent hepatitis C virus NS5A inhibitor |
| Authors: | Lin, HM;Wang, JC;Hu, HS;Wu, PS;Yang, CC;Wu, CP;Pu, SY;Hsu, TA;Jiaang, WT;Chao, YS;Chern, JH;Yeh, TK;Yueh, A |
| Contributors: | Institute of Biotechnology and Pharmaceutical Research |
| 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 structure by means of utilizing a cell-based HCV replicon system. The compound reduced the reporter expression of the HCV1b replicon with an 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 interferon alpha (IFN-alpha), 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 presented an effective small-molecule inhibitor, BP008, potentially targeting at HCV NS5A. BP008 can be considered as part of a more effective therapeutic strategy for HCV in the future. |
| Date: | 2012-01 |
| Relation: | Antimicrobial Agents and Chemotherapy. 2012 Jan;56(1):44-53. |
| Link to: | http://dx.doi.org/10.1128/aac.00599-11 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0066-4804&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000298404900006 |
| Cited Times(Scopus): | http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84455161734 |
| Appears in Collections: | [岳嶽] 期刊論文
[葉燈光] 期刊論文
[陳志豪] 期刊論文
[趙宇生(2002-2013)] 期刊論文
[蔣維棠] 期刊論文
[徐祖安] 期刊論文
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Files in This Item:
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Description |
Size | Format | |
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| PUB22006008.pdf | | 448Kb | Adobe PDF | 793 | View/Open |
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