Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model
Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model
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DOI：
10.1128/aac.00723-07
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发表时间：
2007-12-01
影响因子：
4.9
通讯作者：
Molla, Akhteruzzaman
中科院分区：
文献类型：
--
作者：
Chen, Chih-Ming;He, Yupeng;Molla, Akhteruzzaman
A-837093是丙型肝炎病毒（HCV）非结构蛋白5 B（NS 5 B）RNA依赖性RNA聚合酶的强效特异性非核苷抑制剂。它在酶和基于复制子的细胞培养测定中均具有纳摩尔效力。在大鼠和狗中，该化合物的口服血浆半衰期大于7 It，其生物利用度> 60%。在猴子中，它的半衰期为1.9小时，生物利用度为15%。在一项概念验证研究中，在两只感染HCV的黑猩猩中评估了其抗病毒疗效。该设计包括口服给药30 mg/kg体重，每日两次，持续14天，随后进行14天的给药后观察。在治疗开始后2天内，观察到基因型Ia和1b感染的黑猩猩的最大病毒载量分别降低了1.4和2.5 log，，拷贝RNA/ml。在病毒载量最初下降后，在基因型1b感染的黑猩猩中观察到血浆HCV RNA的反弹，而基因型la感染的黑猩猩经历了持续整个治疗期间的部分反弹。对A-837093处理黑猩猩血浆中的NS 5 B基因序列进行克隆分析，发现存在与A-837093耐药性相关的几种突变，包括基因型Ia感染黑猩猩中的Y 448 H、G554 D和D559 G，以及基因型1b感染黑猩猩中的C316 Y和G554 D。在这两种黑猩猩中鉴定出的耐药相关突变与体外选择研究的结果一致，在体外选择研究中选择了许多相同的突变。这些发现验证了苯并噻二嗪HCV聚合酶抑制剂在体内的抗病毒功效和耐药性发展。
A-837093 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of greater than 7 It, and its bioavailability was > 60%. In monkeys it had a half-life of 1.9 h and 15% bioavailability. Its antiviral efficacy was evaluated in two chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg of body weight twice a day for 14 days, followed by a 14-day posttreatment observation. Maximum viral load reductions of 1.4 and 2.5 log,, copies RNA/ml for genotype la-and 1b-infected chimpanzees, respectively, were observed within 2 days after the initiation of treatment. After this initial drop in the viral load, a rebound of plasma HCV RNA was observed in the genotype 1b-infected chimpanzee, while the genotype la-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period. Clonal analysis of NS5B gene sequences derived from the plasma of A-837093 -treated chimpanzees revealed the presence of several mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the genotype la-infected chimpanzee and C316Y and G554D in the genotype 1b-infected chimpanzee. The identification of resistance-associated mutations in both chimpanzees is consistent with the findings of in vitro selection studies, in which many of the same mutations were selected. These findings validate the antiviral efficacy and resistance development of benzothiadiazine HCV polymerase inhibitors in vivo.