Inhibition of hepatitis B virus replication by N-hydroxyisoquinolinediones and related polyoxygenated heterocycles.
Inhibition of hepatitis B virus replication by N-hydroxyisoquinolinediones and related polyoxygenated heterocycles.
复制标题
DOI：
10.1016/j.antiviral.2017.04.012
复制
发表时间：
2017-07
影响因子：
7.6
通讯作者：
Tavis JE
中科院分区：
文献类型：
--
作者：
Edwards TC;Lomonosova E;Patel JA;Li Q;Villa JA;Gupta AK;Morrison LA;Bailly F;Cotelle P;Giannakopoulou E;Zoidis G;Tavis JE
我们以前报道过B型肝炎病毒（HBV）核糖核酸酶H（RNaseH）对N-羟基异喹啉二酮（HID）化合物抑制的敏感性较低。随后，发现我们的生化RNaseH检测在预测HBV复制抑制方面具有较高的假阴性率，导致低估了抑制HBV复制的HID的数量。在这里，39 HID化合物和结构上相关的多氧杂环（POH），N-羟基吡啶二酮（HPD），和氟酰亚胺进行了筛选，在体外抑制HBV复制。抑制HBV RNaseH优先阻断正极性DNA链的合成，并导致RNA：DNA异源双链体的积累。11种HID和1种HPD优先抑制HBV正极性DNA链积累。EC 50范围为0.69 μM至19 μM，治疗指数为2.4 - 71。HID和HPD对聚合酶延长衣壳中DNA链的能力都没有影响。通过改进的RNA酶H测定和通过检测来自用代表性HID处理的细胞的HBV衣壳中的RNA：DNA异源双链体的积累来证实HID对HBV RNA酶H的抑制。因此，HID支架比我们最初报道的更有希望用于抗HBV药物的发现，并且HPD支架可能具有抗病毒开发的潜力。初步的构效关系将指导HID/HPD作为HBV抑制剂的优化。
We previously reported low sensitivity of the hepatitis B virus (HBV) ribonuclease H (RNaseH) enzyme to inhibition by N-hydroxyisoquinolinedione (HID) compounds. Subsequently, our biochemical RNaseH assay was found to have a high false negative rate for predicting HBV replication inhibition, leading to underestimation of the number of HIDs that inhibit HBV replication. Here, 39 HID compounds and structurally related polyoxygenated heterocycles (POH), N-hydroxypyridinediones (HPD), and flutimides were screened for inhibition of HBV replication in vitro. Inhibiting the HBV RNaseH preferentially blocks synthesis of the positive-polarity DNA strand and causes accumulation of RNA:DNA heteroduplexes. Eleven HIDs and one HPD preferentially inhibited HBV positive-polarity DNA strand accumulation. EC50s ranged from 0.69 μM to 19 μM with therapeutic indices from 2.4 – 71. Neither the HIDs nor the HPD had an effect on the ability of the polymerase to elongate DNA strands in capsids. HBV RNaseH inhibition by the HIDs was confirmed with an improved RNaseH assay and by detecting accumulation RNA:DNA heteroduplexes in HBV capsids from cells treated with a representative HID. Therefore, the HID scaffold is more promising for anti-HBV drug discovery than we originally reported, and the HPD scaffold may hold potential for antiviral development. The preliminary structure-activity relationship will guide optimization of the HID/HPDs as HBV inhibitors.
登录
查看更多内容
影响因子：
4
作者：
Desimmie, Belete A.;Demeulemeester, Jonas;Christ, Frauke
通讯作者：
Christ, Frauke
影响因子：
4.9
作者：
Lu, Gaofeng;Lomonosova, Elena;Tavis, John E.
通讯作者：
Tavis, John E.
影响因子：
5.4
作者：
Gerelsaikhan, T;Tavis, JE;Bruss, V
通讯作者：
Bruss, V
影响因子：
7.3
作者：
Kirschberg, Thorsten A.;Balakrishnan, Mini;Lansdon, Eric B.
通讯作者：
Lansdon, Eric B.
影响因子：
5.4
作者：
Nguyen, David H.;Gummuluru, Suryaram;Hu, Jianming
通讯作者：
Hu, Jianming