Evaluating the role of macrocycles in the susceptibility of hepatitis C virus NS3/4A protease inhibitors to drug resistance.
Evaluating the role of macrocycles in the susceptibility of hepatitis C virus NS3/4A protease inhibitors to drug resistance.
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DOI：
10.1021/cb400100g
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发表时间：
2013-07-19
影响因子：
4
通讯作者：
Schiffer, Celia A.
中科院分区：
文献类型：
--
作者：
Ali, Akbar;Aydin, Cihan;Gildemeister, Reinhold;Romano, Keith P.;Cao, Hong;Oezen, Ayseguel;Soumana, Djade;Newton, Alicia;Petropoulos, Christos J.;Huang, Wei;Schiffer, Celia A.
丙型肝炎病毒(丙型肝炎病毒)感染全球约1.5亿人，是病毒性肝炎、肝硬变和肝癌的主要原因。现有的抗病毒疗法，包括聚乙二醇化干扰素、利巴韦林和一种丙型肝炎病毒NS3/4A蛋白酶抑制剂替拉普韦或博西普韦，对一些患者无效，并导致严重的副作用。更有效的NS3/4A酶抑制剂正在临床开发中，但这些药物的长期有效性受到耐药性发展的挑战。在这里，我们研究了大环在Asunapvir、Danopvir、Vaniprevir和MK-5172中NS3/4A蛋白酶抑制剂对耐药性的敏感性中所起的作用，这些药物具有相似的核心结构，但P2部分和大环化不同。设计、合成了这些药物的线性和大环类似物，并对野生型和耐药变异体R155K、V36M/R155K、A156T和D168A进行了酶分析和抗病毒试验。大环抑制剂通常更有效，但大环的位置对于保持对耐药变异体的活性至关重要--P1-P3大环抑制剂比线性和P2-P4大环类似物对耐药性的敏感性较低。此外，P2处的杂环部分在很大程度上决定了抑制剂的耐药性、耐药性的敏感性以及解旋酶结构域的调节程度。我们的发现表明，为了设计对耐药的NS3/4A蛋白酶变体保持效力的强效抑制剂，抑制剂应该将P1-P3大环与灵活的P2部分结合起来，这些部分最好地与该酶的恒定催化三联体接触。
The hepatitis C virus (HCV) infects an estimated 150 million people worldwide and is the major cause of viral hepatitis, cirrhosis and liver cancer. The available antiviral therapies, which include pegylated-interferon, ribavirin and one of the HCV NS3/4A protease inhibitors telaprevir or boceprevir, are ineffective for some patients and cause severe side effects. More potent NS3/4A protease inhibitors are in clinical development, but the long-term effectiveness of these drugs is challenged by the development of drug resistance. Here, we investigated the role of macrocycles in the susceptibility of NS3/4A protease inhibitors to drug resistance in asunaprevir, danoprevir, vaniprevir, and MK-5172, with similar core structures but varied P2 moieties and macrocyclizations. Linear and macrocyclic analogues of these drugs were designed, synthesized and tested against wild-type and drug-resistant variants R155K, V36M/R155K, A156T, and D168A in enzymatic and antiviral assays. Macrocyclic inhibitors were generally more potent, but the location of the macrocycle was critical for retaining activity against drug-resistant variants – the P1–P3 macrocyclic inhibitors were less susceptible to drug resistance than the linear and P2–P4 macrocyclic analogues. In addition, the heterocyclic moiety at P2 largely determined the inhibitor resistance profile, susceptibility to drug resistance, and the extent of modulation by the helicase domain. Our findings suggest that to design robust inhibitors that retain potency to drug resistant NS3/4A protease variants, inhibitors should combine P1–P3 macrocycles with flexible P2 moieties that optimally contact with the invariable catalytic triad of this enzyme.
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