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标题: AB-506 的临床前表征，一种靶向病毒核心蛋白的 HBV 复制抑制 [打印本页]

作者: StephenW 时间: 2021-11-28 04:14 标题: AB-506 的临床前表征，一种靶向病毒核心蛋白的 HBV 复制抑制

抗病毒药物

. 2021 年 11 月 23 日；105211。
doi：10.1016/j.antiviral.2021.105211。印刷前在线。
AB-506 的临床前表征，一种靶向病毒核心蛋白的 HBV 复制抑制剂
Nagraj Mani 1 , Andrew G Cole 2 , Janet R Phelps 2 , Andrzej Ardzinski 2 , Robbin Burns 2 , Tim Chiu 2 , Andrea Cuconati 2 , Bruce D Dorsey 2 , Ellen Evangelista 2 , Kristi Fan 2 , Trofang Guo Harasym 2 2、萨拉姆·卡迪姆 2、罗珊·科瓦尔斯基 2、史蒂文·G·库尔特根 2、艾米·CH·李 2、爱丽丝 H Li 2、萨拉·马耶斯基 2、安吉拉·米勒 2、克里斯·帕塞特卡 2、斯蒂芬·P·里德 2、雷内·里金布兰德 2、霍莉·米科洛奇克Steuer 2 , Kim Stever 2 , Sunny Tang 2 , Xiaowei Teng 2 , Xiaohe Wang 2 , Michael J Sofia 2
隶属关系
隶属关系

1
Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA。电子地址：[email protected]。
2
Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA。

PMID：34826506 DOI：10.1016/j.antiviral.2021.105211

抽象的

AB-506 是一种靶向 HBV 核心蛋白的小分子抑制剂，可在体外（HepAD38 细胞：EC50 为 0.077 μM，CC50 > 25 μM）和体内（HBV 小鼠模型：血清 HBV DNA 降低约 3.0 log10 降低）抑制病毒复制与车辆控制相比）。 AB-506 与 HBV 核心蛋白的结合可加速衣壳组装并抑制 HBV pgRNA 衣壳化。此外，AB-506 可阻断 HBV 感染的 HepG2-hNTCP-C4 细胞和原代人肝细胞中的 cccDNA 建立，从而抑制病毒 RNA、HBsAg 和 HBeAg 的产生（EC50 从 0.64 μM 到 1.92 μM）。 AB-506 表现出对 HBV 基因型 A-H 的活性，并在体外保持对核苷（酸）类似物抗性变体的抗病毒活性。针对一组核心变体对 AB-506 的评估表明，T33N/Q 替换导致 EC50 值增加 > 200 倍，而 L30F、L37Q 和 I105T 替换显示 EC50 值增加了 8 到 20 倍，相比之下野生型。 AB-506 与 NAs 或 RNAi 试剂的体外组合具有适度的协同作用。 AB-506 在啮齿类动物中表现出良好的口服生物利用度、全身暴露和更高的肝脏与血浆比率，这是支持慢性乙型肝炎临床开发的药代动力学特征。

关键词：AB-506；氨基茚满；乙肝;衣壳抑制剂；乙肝病毒； pgRNA 衣壳化。

版权所有 © 2021。Elsevier B.V. 出版
利益冲突声明

利益声明作者声明以下可能被视为潜在竞争利益的经济利益/个人关系：作者包括 Arbutus Biopharma Inc. 的现任或前任员工，并且可能拥有公司股票和/或专利。

作者: StephenW 时间: 2021-11-28 04:14

Antiviral Res

. 2021 Nov 23;105211.
doi: 10.1016/j.antiviral.2021.105211. Online ahead of print.
Preclinical characterization of AB-506, an inhibitor of HBV replication targeting the viral core protein
Nagraj Mani 1 , Andrew G Cole 2 , Janet R Phelps 2 , Andrzej Ardzinski 2 , Robbin Burns 2 , Tim Chiu 2 , Andrea Cuconati 2 , Bruce D Dorsey 2 , Ellen Evangelista 2 , Kristi Fan 2 , Fang Guo 2 , Troy O Harasym 2 , Salam Kadhim 2 , Roseann Kowalski 2 , Steven G Kultgen 2 , Amy C H Lee 2 , Alice H Li 2 , Sara A Majeski 2 , Angela Miller 2 , Chris Pasetka 2 , Stephen P Reid 2 , Rene Rijnbrand 2 , Holly M Micolochick Steuer 2 , Kim Stever 2 , Sunny Tang 2 , Xiaowei Teng 2 , Xiaohe Wang 2 , Michael J Sofia 2
Affiliations
Affiliations

1
Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA. Electronic address: [email protected].
2
Arbutus Biopharma Inc., 701 Veterans Circle, Warminster, PA, 18974, USA.

PMID: 34826506 DOI: 10.1016/j.antiviral.2021.105211

Abstract

AB-506, a small-molecule inhibitor targeting the HBV core protein, inhibits viral replication in vitro (HepAD38 cells: EC50 of 0.077 μM, CC50 > 25 μM) and in vivo (HBV mouse model: ∼3.0 log10 reductions in serum HBV DNA compared to the vehicle control). Binding of AB-506 to HBV core protein accelerates capsid assembly and inhibits HBV pgRNA encapsidation. Furthermore, AB-506 blocks cccDNA establishment in HBV-infected HepG2-hNTCP-C4 cells and primary human hepatocytes, leading to inhibition of viral RNA, HBsAg, and HBeAg production (EC50 from 0.64 μM to 1.92 μM). AB-506 demonstrated activity across HBV genotypes A-H and maintains antiviral activity against nucleos(t)ide analog-resistant variants in vitro. Evaluation of AB-506 against a panel of core variants showed that T33N/Q substitutions results in >200-fold increase in EC50 values, while L30F, L37Q, and I105T substitutions showed an 8 to 20-fold increase in EC50 values in comparison to the wild-type. In vitro combinations of AB-506 with NAs or an RNAi agent were additive to moderately synergistic. AB-506 exhibits good oral bioavailability, systemic exposure, and higher liver to plasma ratios in rodents, a pharmacokinetic profile supporting clinical development for chronic hepatitis B.

Keywords: AB-506; Aminoindane; CHB; Capsid inhibitor; HBV; pgRNA encapsidation.

Copyright © 2021. Published by Elsevier B.V.
Conflict of interest statement

Declaration of interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Authors include current or former employees of Arbutus Biopharma Inc., and may own company stock and/or patents.

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