The cyclophilin inhibitor debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus
The cyclophilin inhibitor debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus
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DOI：
10.1002/hep.22131
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发表时间：
2008-03-01
期刊：
影响因子：
13.5
通讯作者：
Scalfaro, Pietro
中科院分区：
文献类型：
--
作者：
Flisiak, Robert;Horban, Andrzej;Scalfaro, Pietro
Debio-025 是一种口服亲环蛋白 (Cyp) 抑制剂，在体外具有有效的抗丙型肝炎病毒活性。在一项随机、双盲、安慰剂对照研究中研究了它对病毒载量的影响以及对细胞内 Cyp 水平的影响。每日两次 1200 mg 口服治疗 14 天后，平均丙型肝炎病毒载量显着下降 3.6 log(10) (P < 0.0001)，对研究中代表的 3 种基因型（1、3 和 4）有作用。此外，治疗期间没有出现病毒反弹，表明Debio-025对于耐药性的选择具有很高的屏障。在接受 Debio-025 治疗的患者中，第 15 天时外周血单核细胞中的亲环蛋白 B (CypB) 水平从 67 +/- 6（标准误差）ng/mg 蛋白（基线）下降至 5 +/- 1 ng/mg 蛋白（P < 0.01）。结论：Debio-025 引起 CypB 水平大幅下降，与丙型肝炎病毒载量的下降同时发生。这些是第一个初步的人体数据，支持以下假设：CypB 可能在丙型肝炎病毒复制中发挥重要作用，并且 Cyp 抑制是开发抗丙型肝炎药物的有效目标。
Debio-025 is an oral cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus activity in vitro. Its effect on viral load as well as its influence on intracellular Cyp levels was investigated in a randomized, double-blind, placebo-controlled study. Mean hepatitis C viral load decreased significantly by 3.6 log(10) after a 14-day oral treatment with 1200 mg twice daily (P < 0.0001) with an effect against the 3 genotypes (1, 3, and 4) represented in the study. In addition, the absence of viral rebound during treatment indicates that Debio-025 has a high barrier for the selection of resistance. In Debio-025-treated patients, cyclophilin B (CypB) levels in peripheral blood mononuclear cells decreased from 67 +/- 6 (standard error) ng/mg protein (baseline) to 5 +/- 1 ng/mg protein at day 15 (P < 0.01). Conclusion: Debio-025 induced a strong drop in CypB levels, coinciding with the decrease in hepatitis C viral load. These are the first preliminary human data supporting the hypothesis that CypB may play an important role in hepatitis C virus replication and that Cyp inhibition is a valid target for the development of anti-hepatitis C drugs.