In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS5A Inhibitor Pibrentasvir.
In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS5A Inhibitor Pibrentasvir.
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DOI：
10.1128/aac.02558-16
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发表时间：
2017-05
影响因子：
4.9
通讯作者：
Collins C
中科院分区：
文献类型：
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作者：
Ng TI;Krishnan P;Pilot-Matias T;Kati W;Schnell G;Beyer J;Reisch T;Lu L;Dekhtyar T;Irvin M;Tripathi R;Maring C;Randolph JT;Wagner R;Collins C
吡布伦塔韦(ABT-530)是一种新型的泛基因型丙型肝炎病毒(HCV)NS5A抑制剂，对1~6型丙型肝炎病毒复制子的半数有效浓度(EC50)为1.4~5.0 pm。临床标本中的1~6型丙型肝炎病毒NS5A嵌合复制子也显示出类似的活性。使用来自1a、1b、2a、2b、3a、4a、5a或6a的NS5A的丙型肝炎病毒复制子细胞进行耐药性选择研究，其浓度是各自复制子的EC50的10倍或100倍。在吡布曲韦的EC50为10倍的情况下，在含有1a、2a或3a型NS5A的复制子中只选择了少量具有抗性相关氨基酸替换的菌落(占输入细胞的0.00015~0.0065%)，而在含有来自其他基因型的NS5A的复制子中没有选择存活的菌落。在1a基因复制子细胞中，匹布列韦选择了极少的克隆(占输入细胞的0.0002%)，而在其他复制子中没有选择克隆。Pibrentasvir对其他NS5A抑制剂包括关键氨基酸28、30、31或93位的丙型肝炎病毒1至6型中常见的导致耐药性的替换具有活性。吡布列韦与其他类别的丙型肝炎病毒抑制剂联合使用，产生了协同抑制丙型肝炎病毒复制的作用。综上所述，匹布列韦是一种新一代丙型肝炎病毒NS5A抑制剂，具有强大的泛基因活性，并对已知对目前批准的NS5A抑制剂具有耐药性的1至6型丙型肝炎病毒的常见氨基酸替换保持活性。
Pibrentasvir (ABT-530) is a novel and pan-genotypic hepatitis C virus (HCV) NS5A inhibitor with 50% effective concentration (EC50) values ranging from 1.4 to 5.0 pM against HCV replicons containing NS5A from genotypes 1 to 6. Pibrentasvir demonstrated similar activity against a panel of chimeric replicons containing HCV NS5A of genotypes 1 to 6 from clinical samples. Resistance selection studies were conducted using HCV replicon cells with NS5A from genotype 1a, 1b, 2a, 2b, 3a, 4a, 5a, or 6a at a concentration of pibrentasvir that was 10- or 100-fold over its EC50 for the respective replicon. With pibrentasvir at 10-fold over the respective EC50, only a small number of colonies (0.00015 to 0.0065% of input cells) with resistance-associated amino acid substitutions were selected in replicons containing genotype 1a, 2a, or 3a NS5A, and no viable colonies were selected in replicons containing NS5A from other genotypes. With pibrentasvir at 100-fold over the respective EC50, very few colonies (0.0002% of input cells) were selected by pibrentasvir in genotype 1a replicon cells while no colonies were selected in other replicons. Pibrentasvir is active against common resistance-conferring substitutions in HCV genotypes 1 to 6 that were identified for other NS5A inhibitors, including those at key amino acid positions 28, 30, 31, or 93. The combination of pibrentasvir with HCV inhibitors of other classes produced synergistic inhibition of HCV replication. In summary, pibrentasvir is a next-generation HCV NS5A inhibitor with potent and pan-genotypic activity, and it maintains activity against common amino acid substitutions of HCV genotypes 1 to 6 that are known to confer resistance to currently approved NS5A inhibitors.