Reply to Padmanabhan and Dixit: Hepatitis C virus entry inhibitors for optimally boosting direct-acting antiviral-based treatments.
Reply to Padmanabhan and Dixit: Hepatitis C virus entry inhibitors for optimally boosting direct-acting antiviral-based treatments.
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回复 Padmanabhan 和 Dixit：丙型肝炎病毒进入抑制剂，可最佳地促进基于直接抗病毒的治疗。
DOI：
10.1073/pnas.1705234114
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Watashi K
中科院分区：
文献类型：
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作者：
Ohashi HK;Koizumi Y;Fukano K;Wakita T;Perelson AS;Iwami S;Watashi K
我们感谢Padmanabhan和Dixit对我们的文件(2)提出的意见(1)。他们指出，进入抑制剂可能会形成最佳药物组合的有效合作伙伴。他们分析了之前发表的10种正在临床或临床前开发的丙型肝炎病毒进入抑制剂的数据，发现其中一些丙型肝炎病毒进入抑制剂显示出比直接作用抗病毒药物(DAA)的瞬时抑制势(IIPS)更高的瞬时抑制势(IIPS)(3)。为了进一步分析进入抑制剂与其他DAA联合使用的实用性，并扩展我们的原始结果(2)，我们量化了四种不同类别的进入抑制剂[AR4A(抗丙型肝炎病毒E2抗体)(4)，BLT-1[清道夫受体B型1(SR-BI)抑制剂](5)，erlotinib(EGF受体抑制剂)(6)，和达沙替尼(EphA2抑制剂)(6)单独以及与Padmanabhan和Dixit(1)研究的六种DAA在丙型肝炎病毒感染细胞培养系统中的抗丙型肝炎病毒作用(图1和B)。这些进入抑制剂的单独治疗显示出剂量依赖性的降低丙型肝炎病毒RNA水平。利用中位效应(1-3)，我们从每种药物的剂量-反应曲线(表1)估算了IC50(半数抑制浓度)和m(斜率参数)，这使我们能够计算出当D=100×IC50(即，I.P100)时的IP=log[1+(D/IC50)m](图1C)。我们发现BLT-1在进入抑制剂中表现出最高的i-ip100，其价值与DAAs相当。此外，应用Bliss独立性(7)，我们量化了D=100×IC50(I.P100Bcom)时三种药物治疗的抗丙型肝炎病毒活性上限(图1D)。这些数据清楚地表明，丙型肝炎病毒进入抑制剂增强了双DAA治疗的抗病毒效果。有趣的是，通过加入进入抑制剂来增强抗病毒效果在很大程度上取决于所使用的进入抑制剂：在被测试的进入抑制剂中，包括BLT-1在内的三种药物治疗显示出特别高的I.P100Bcom，这与基于三重DAA的治疗的I.P100Bcom相当。
We thank Padmanabhan and Dixit for their comments (1) on our paper (2). They pointed out that entry inhibitors might form potent partners for optimal drug combinations. They analyzed previously published data on 10 hepatitis C virus (HCV) entry inhibitors that are under clinical or preclinical development and found some of these HCV entry inhibitors showed high instantaneous inhibitory potentials (IIPs)(3) compared with IIPs of direct-acting antivirals (DAAs). To analyze further the utility of combining entry inhibitors with other DAAs and to extend our original results (2), we quantified the anti-HCV effect of four different classes of entry inhibitors [AR4A (anti-HCV E2 antibody)(4), BLT-1 [scavenger receptor class B type 1 (SR-BI) inhibitor](5), erlotinib (EGF receptor inhibitor)(6), and dasatinib (EphA2 inhibitor)(6)] singly and in combination with six DAAs studied by Padmanabhan and Dixit (1) in the HCV infectious cell culture system (Fig. 1 A and B). Single treatment of these entry inhibitors exhibited a dose-dependent reduction in HCV RNA levels. Using the median effect (1–3), we estimated I C 50, the half-maximum inhibitory concentration, and m, the slope parameter, for each drug from its dose–response curve (Table 1), which enables us to calculate I I P= log [1+(D/I C 50) m] at D= 100× I C 50 (ie, I I P 100)(Fig. 1C). We found BLT-1 shows the highest I I P 100 among the entry inhibitors, which is equivalent in value to DAAs. In addition, applying Bliss independence (7), we quantified the upper limits of anti-HCV activity for triple-drug treatments at D= 100× I C 50 (I I P 100 Bcom)(Fig. 1D). These data clearly showed that HCV entry inhibitors augmented the antiviral effect of double DAA-based treatments. Interestingly, augmentation of antiviral effects by addition of entry inhibitors largely depended on the entry inhibitor used: Triple-drug treatments, including BLT-1, showed an especially high I I P 100 Bcom, which is comparable to the I I P 100 Bcom of triple DAA-based treatments, among the tested entry inhibitors.