衣壳装配调节剂的新作用是靶向成熟的乙型肝炎病毒衣壳并

StephenW

Antimicrob Agents Chemother. 2019 Oct 28. pii: AAC.01440-19. doi: 10.1128/AAC.01440-19. [Epub ahead of print]
A new role for capsid assembly modulators to target mature hepatitis B virus capsids and prevent virus infection.
Ko C1, Bester R1, Zhou X2, Xu Z2, Blossey C1, Sacherl J1, Vondran FWR3,4, Gao L2, Protzer U5,6.
Author information

1
    Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany.
2
    Roche Innovation Center Shanghai, Shanghai, China.
3
    ReMediES, Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany.
4
    German Centre for Infection Research (DZIF), partner site Hannover-Braunschweig, Hannover, Germany.
5
    Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany [email protected] [email protected].
6
    German Center for Infection Research (DZIF), Munich partner site, Munich, Germany.

Abstract

Hepatitis B virus (HBV) is a major human pathogen killing an estimated 887,000 humans per year. Therefore, potentially curative therapies are of high need. Following infection, HBV deposits a covalently closed circular (ccc) DNA in the nucleus of infected cells that serves as transcription template and is not affected by current therapies. HBV core protein allosteric modulators (CpAMs) prevent correct capsid assembly but may also affect early stages of HBV infection. In this study, we aimed to determine the antiviral efficacy of a novel, structurally distinct heteroaryldihydropyrimidine (HAP)-type CpAM, HAP_R01, and investigated whether and how HAP_R01 prevents the establishment of HBV infection. HAP_R01 shows a significant inhibition of cccDNA formation when applied during the first 48 h of HBV infection. Inhibiting cccDNA formation, however, requires >1 log10 higher concentrations than inhibition of the assembly of newly forming capsids (half-maximal effective concentration (EC50) 345-918 nM versus 26.8-43.5 nM, respectively). Biophysical studies using a new method to detect the incoming capsid in de novo infection revealed that HAP_R01 can physically change mature capsids of incoming virus particles and affect particle integrity. Treating purified HBV virions with HAP_R01 reduced their infectivity, highlighting the unique antiviral activity of CpAMs to target the capsid within mature HBV particles. Accordingly, HAP_R01 shows an additive antiviral effect in limiting de novo infection when combined with viral entry inhibitors. In summary, HAP_R01 perturbs capsid integrity of incoming virus particle, reduces their infectivity and thus inhibits cccDNA formation in addition to preventing HBV capsid assembly.

Copyright © 2019 American Society for Microbiology.

PMID:
    31658963
DOI:
    10.1128/AAC.01440-19

StephenW

抗微生物剂Chemother。 2019十月28. pii：AAC.01440-19。 doi：10.1128 / AAC.01440-19。 [Epub提前发布]
衣壳装配调节剂的新作用是靶向成熟的乙型肝炎病毒衣壳并防止病毒感染。
Ko C1，Bester R1，Zhou X2，Xu Z2，Blossey C1，Sacherl J1，Vondran FWR3,4，Gao L2，Protzer U5,6。
作者信息

1个
    慕尼黑工业大学病毒学研究所/德国慕尼黑Helmholtz ZentrumMünchen。
2
    上海罗氏创新中心，中国上海。
3
    德国汉诺威汉诺威医学院普通外科，内脏和移植外科系。
4
    德国感染研究中心（DZIF），合作伙伴站点，德国汉诺威，汉诺威-不伦瑞克。
5
    慕尼黑工业大学病毒学研究所/ Helmholtz ZentrumMünchen，德国慕尼黑[email protected] [email protected]。
6
    德国感染研究中心（DZIF），慕尼黑合作伙伴地点，德国慕尼黑。

抽象

乙型肝炎病毒（HBV）是主要的人类病原体，估计每年杀死887,000人。因此，非常需要潜在的治疗方法。感染后，HBV在感染细胞的细胞核中沉积共价闭合的环状（ccc）DNA，该DNA可作为转录模板，不受当前疗法的影响。 HBV核心蛋白变构调节剂（CpAM）阻止正确的衣壳装配，但也可能影响HBV感染的早期阶段。在这项研究中，我们旨在确定新型，结构独特的杂芳基二氢嘧啶（HAP）型CpAM，HAP_R01的抗病毒功效，并研究HAP_R01是否以及如何阻止HBV感染的发生。当在HBV感染的前48小时内使用HAP_R01时，它会显着抑制cccDNA的形成。然而，抑制cccDNA的形成需要比抑制新形成的衣壳装配高1个log10的浓度（半最大有效浓度（EC50）345-918 nM对26.8-43.5 nM）。使用新方法检测从头感染中传入衣壳的生物物理研究表明，HAP_R01可以物理改变传入病毒颗粒的成熟衣壳并影响颗粒完整性。用HAP_R01处理纯化的HBV病毒颗粒可降低其感染性，突出了CpAM靶向成熟HBV颗粒衣壳的独特抗病毒活性。因此，当与病毒进入抑制剂组合使用时，HAP_R01在限制从头感染中显示出附加的抗病毒作用。总之，HAP_R01扰乱了传入病毒颗粒的衣壳完整性，降低了它们的感染力，因此除了防止HBV衣壳装配外，还抑制了cccDNA的形成。

版权所有©2019美国微生物学会。

PMID：
    31658963
DOI：
    10.1128 / AAC.01440-19

newchinabok

防止HBV衣壳装配外，还抑制了cccDNA的形成。

newchinabok

最后还需要双免疫疗法毕其功于一役