國家衛生研究院 NHRI:Item 3990099045/6878
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    題名: Resistance studies of a di-thiazol analogue, DBPR110, as a potential hepatitis C virus NS5A inhibitor in replicon systems
    作者: Lin, HM;Wang, JC;Hu, HS;Wu, PS;Wang, WH;Wu, SY;Yang, CC;Yeh, TK;Hsu, TA;Jiaang, WT;Chao, YS;Chern, JH;Yueh, A
    貢獻者: Institute of Biotechnology and Pharmaceutical Research
    摘要: Hepatitis C virus (HCV), a member of the Flaviviridae family, affects approximately 3% of the world's population and is becoming the leading cause of liver disease in the world. Therefore, the development of novel or more effective treatment strategies to treat chronic HCV infection is urgently needed. In our previous study, we have identified a potential HCV NS5A inhibitor, BP008. After further systemic optimization, we discovered a more potent HCV inhibitor, DBPR110. DBPR110 reduced the reporter expression of the HCV1b replicon with an EC(50) and a selective index value of 3.9 +/- 0.9 pM and > 12,800,000, respectively. DBPR110 reduced HCV2a replicon activity with an EC(50) and a selective index value of 228.8 +/- 98.4 pM and >173,130, respectively. Sequencing analyses of several individual clones derived from the DBPR110-resistant RNAs purified from cells harboring genotype 1b and 2a HCV replicon revealed that amino acid substitutions mainly within the N-terminal region (domain I) of NS5A were associated with decreased inhibitor susceptibility. P58L/T and Y93H/N in genotype 1b and T24A, P58L and Y93H in the genotype 2a replicon were the key substitutions for resistance selection. In the 1b replicon, V153M, M202L and M265V play a compensatory role in the replication and drug resistance. Moreover, DBPR110 displayed synergistic effects with IFN-alpha, an NS3 protease inhibitor, and an NS5B polymerase inhibitor. In summary, our results present an effective small-molecule inhibitor, DBPR110 that potentially targets HCV NS5A. DBPR110 could be part of a more effective therapeutic strategy for HCV in the future.
    日期: 2013-02
    關聯: Antimicrobial Agents and Chemotherapy. 2013 Feb; 57(2):723-733.
    Link to: http://dx.doi.org/10.1128/aac.01403-12
    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:000313896500006
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84872836019
    顯示於類別:[岳嶽] 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
    [伍素瑩] 期刊論文
    [葉燈光] 期刊論文

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