核心蛋白质变构调节剂直接抑制乙型肝炎病毒e抗原。

StephenW

Hepatology. 2019 Jan 21. doi: 10.1002/hep.30514. [Epub ahead of print]
Direct inhibition of hepatitis B virus e antigen by core protein allosteric modulator.
Yan Z1, Wu D1, Hu H1, Zeng J1, Yu X1, Xu Z1, Zhou Z1, Zhou X1, Yang G1, Young JAT2, Gao L1.
Author information

1
    Roche Innovation Center Shanghai, Shanghai, 201203, China.
2
    Roche Innovation Center Basel, 4070, Basel, Switzerland.

Abstract

Hepatitis B e antigen (HBeAg) is an important immunomodulator for promoting host immune tolerance during chronic hepatitis B (CHB) infection. In CHB patients, HBeAg loss and seroconversion represent partial immune control of CHB infection and are regarded as valuable endpoints. However, the current approved treatments have only a limited efficacy in achieving HBeAg seroconversion in HBeAg-positive patients. HBV core protein has been recognized as an attractive antiviral target and two classes of core protein allosteric modulator (CpAM) have been discovered: the phenylpropenamides (PPAs) and the heteroaryldihydropyrimidines (HAPs). However, their differentiation and potential therapeutic benefit beyond HBV DNA inhibition remain to be seen. Here, we show that in contrast to PPA series compound AT-130, a novel HAP CpAM, HAP_R01, reduced HBeAg levels in multiple in vitro and in vivo HBV experimental models. Mechanistically, we found that HAP_R01 treatment caused the misassembly of capsids formed by purified HBeAg in vitro. In addition, HAP_R01 directly reduces HBeAg levels by inducing intracellular precore protein misassembly and aggregation. Using a HAP_R01 resistant mutant, we found that this HAP_R01-mediated HBeAg and core reductions were mediated via the same mechanism. Furthermore, HAP_R01 treatment substantially reduced serum HBeAg levels in an HBV mouse model. Conclusion Unlike PPA series compound AT-130, HAP_R01 not only inhibits HBV DNA levels, but also directly reduces HBeAg via induction of its misassembly. HAP_R01, as well as other similar CpAMs, have the potential to achieve higher anti-HBeAg seroconversion rates than currently approved therapies for CHB patients. Our findings also provide guidance for dose selection when designing clinical trials with molecules from HAP series. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.
KEYWORDS:

HAP ; CpAM; HBV capsid; HBeAg reduction; precore

PMID:
    30664279
DOI:
    10.1002/hep.30514

StephenW

肝病。 2019年1月21日doi：10.1002 / hep.30514。 [印刷前的电子版]
核心蛋白质变构调节剂直接抑制乙型肝炎病毒e抗原。
严Z1，吴D1，胡H1，曾J1，于X1，徐Z1，周Z1，周X1，杨G1，杨JAT2，高L1。
作者信息

1
    罗氏创新中心，上海，201203，中国。
2
    罗氏创新中心巴塞尔，4070，瑞士巴塞尔。

抽象

乙型肝炎e抗原（HBeAg）是一种重要的免疫调节剂，用于在慢性乙型肝炎（CHB）感染期间促进宿主免疫耐受。在CHB患者中，HBeAg丢失和血清转换代表CHB感染的部分免疫控制，并被认为是有价值的终点。然而，目前批准的治疗在HBeAg阳性患者中实现HBeAg血清转换的效果有限。 HBV核心蛋白已被公认为具有吸引力的抗病毒靶标，已发现两类核心蛋白质变构调节剂（CpAM）：苯基丙烯酰胺（PPAs）和杂芳基二氢嘧啶（HAPs）。然而，它们的分化和超出HBV DNA抑制的潜在治疗益处仍有待观察。在这里，我们显示与PPA系列化合物AT-130相比，新型HAP CpAM，HAP_R01，降低了多种体外和体内HBV实验模型中的HBeAg水平。在机理上，我们发现HAP_R01处理导致由体外纯化的HBeAg形成的衣壳的错误组装。此外，HAP_R01通过诱导细胞内前核心蛋白质错误组装和聚集直接降低HBeAg水平。使用HAP_R01抗性突变体，我们发现这种HAP_R01介导的HBeAg和核心减少是通过相同的机制介导的。此外，HAP_R01治疗显着降低了HBV小鼠模型中的血清HBeAg水平。结论与PPA系列化合物AT-130不同，HAP_R01不仅可抑制HBV DNA水平，还可通过诱导其错误组装直接降低HBeAg。 HAP_R01以及其他类似的CpAM可能比目前批准的CHB患者疗法具有更高的抗HBeAg血清转换率。我们的研究结果还为使用HAP系列分子设计临床试验时的剂量选择提供了指导。本文受版权保护。版权所有。

本文受版权保护。版权所有。
关键词：

HAP; CPAM; HBV衣壳; HBeAg减少;前C区

结论：
    30664279
DOI：
    10.1002 / hep.30514

newchinabok

期待核衣壳长期抗病毒效果，比如3，5年，短期抗病毒已明了。免疫药是短板呀

StephenW

预计HAP-R01可降低血清hbvdna, 但如果HAP-R01还能降低血清HBsAg，这种临床意义尚不清楚:
1. 是否可以导致从HbeAg阳性变为HBeAg阴性?
2. 是否可以导致不活跃小三阳? - 如果它导致核心蛋白的耗尽，它也可能减少HBcAg特异性T细胞用于控制HBV感染.