An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus
An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus
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DOI：
10.1038/nature02099
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发表时间：
2003-11-13
期刊：
影响因子：
64.8
通讯作者：
Llinàs-Brunet, M
中科院分区：
文献类型：
--
作者：
Lamarre, D;Anderson, PC;Llinàs-Brunet, M
丙型肝炎病毒（HCV）感染是全球慢性肝病的一个严重原因，超过1.7亿感染者有发生显著发病率和死亡率的风险（1-3）。目前基于干扰素的治疗（4）是次优的，特别是在感染HCV基因型1的患者中，并且它们的耐受性差，突出了对新疗法的未满足的医疗需求（5，6）。HCV编码的NS 3蛋白酶是病毒复制所必需的（7，8），并且长期以来一直被认为是HCV感染患者中治疗干预的有吸引力的靶标。在这里，我们确定了一类特异性和有效的NS 3蛋白酶抑制剂，并报告了BILN 2061的评价，BILN 2061是一种通过口服摄入生物学上可获得的小分子抑制剂，也是同类药物中第一个进行人体试验的药物。对感染HCV基因型1的患者给予BILN 2061 2天，导致HCV RNA血浆水平显著降低，并建立了HCV NS 3蛋白酶抑制剂在人体中的概念验证。我们的研究结果进一步说明了潜在的病毒酶靶向药物发现方法的发展新的HCV治疗。
Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality(1-3). Current interferon-based therapies(4) are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics(5,6). The HCV-encoded NS3 protease is essential for viral replication(7,8) and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.