新型的乙型肝炎病毒衣壳装配调节剂在体外和人源化小鼠中

StephenW

Antimicrob Agents Chemother. 2019 Nov 11. pii: AAC.01701-19. doi: 10.1128/AAC.01701-19. [Epub ahead of print]
Novel Hepatitis B Virus Capsid Assembly Modulator Induces Potent Antiviral Responses in Vitro and in Humanized Mice.
Amblard F1, Boucle S1, Bassit L1, Cox B1, Sari O1, Tao S1, Chen Z1, Ozturk T1, Verma K1, Russell O1, Rat V2, de Rocquigny H2, Fiquet O3,4, Boussand M3,4, Di Santo J3,4, Strick-Marchand H3,4, Schinazi RF5.
Author information

1
    Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive, Atlanta, GA 30322, USA.
2
    Morphogenèse et Antigénicité du VIH et des Virus des Hépatites, Inserm - U1259 MAVIVH, Hôpital Bretonneau, 10 boulevard Tonnellé - BP 3223 37032 Tours Cedex 1, France.
3
    Innate Immunity Unit, Institut Pasteur, 75724 Paris, France.
4
    Inserm U1223, 75724 Paris, France.
5
    Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive, Atlanta, GA 30322, USA [email protected].

Abstract

Hepatitis B virus (HBV) affects an estimated 250 million chronic carriers worldwide. Though several vaccines exist, they are ineffective for those already infected. HBV persists due to the formation of covalently-closed circular DNA (cccDNA) - the viral minichromosome - in the nucleus of hepatocytes. Current nucleoside analogs and interferon therapies rarely clear cccDNA, requiring lifelong treatment. Our group identified GLP-26, a novel glyoxamide derivative that alters HBV nucleocapsid assembly and prevents viral DNA replication. GLP-26 exhibited single-digit nanomolar anti-HBV activity and inhibition of HBeAg secretion, and reduced cccDNA amplification in addition to a promising pre-clinical profile. Strikingly, long term combination treatment with entecavir in a humanized mouse model induced decrease in viral loads and viral antigens that was sustained for up to 12 weeks after treatment cessation.

Copyright © 2019 American Society for Microbiology.

PMID:
    31712213
DOI:
    10.1128/AAC.01701-19

StephenW

抗微生物剂Chemother。 2019年11月11日.pii：AAC.01701-19。 doi：10.1128 / AAC.01701-19。 [Epub提前发布]
新型的乙型肝炎病毒衣壳装配调节剂在体外和人源化小鼠中诱导有效的抗病毒反应。
Amblard F1，Boucle S1，Bassit L1，Cox B1，Sari O1，Tao S1，Chen Z1，Ozturk T1，Verma K1，Russell O1，Rat V2，de Rocquigny H2，Fiquet O3,4，Boussand M3,4，Di Santo J3 ，4，Strick-Marchand H3,4，Schinazi RF5。
作者信息

1个
    艾默里大学医学院儿科生化药理学实验室艾滋病研究中心，美国佐治亚州亚特兰大市海德古德大道1760号，乔治亚州30322。
2
    MorphogenèseetAntigénicitédu VIH et Virus desHépatites，Inserm-U1259 MAVIVH，HôpitalBretonneau，10林荫大道Tonnellé-BP 3223 37032游览法国Cedex 1。
3
    巴斯德研究所先天免疫小组，法国巴黎75724。
4
    Inserm U1223，75724巴黎，法国。
5
    艾默里大学医学院儿科生化药理学实验室艾滋病研究中心，美国佐治亚州亚特兰大市海古德道1760号，乔治亚州30322，rschina @ emory.edu。

抽象

乙型肝炎病毒（HBV）影响全球约2.5亿慢性携带者。尽管存在几种疫苗，但它们对已经感染的疫苗无效。 HBV持续存在是由于在肝细胞核中形成了共价闭合的环状DNA（cccDNA）-病毒微染色体。当前的核苷类似物和干扰素疗法很少清除cccDNA，需要终身治疗。我们的小组鉴定出GLP-26，这是一种新型乙二酰胺衍生物，可改变HBV核衣壳装配并防止病毒DNA复制。除了有希望的临床前概况，GLP-26还显示出一位数的纳摩尔抗HBV活性和对HBeAg分泌的抑制作用，并减少了cccDNA的扩增。令人惊讶的是，在人源化小鼠模型中与恩替卡韦进行长期联合治疗可导致病毒载量和病毒抗原的减少，在治疗终止后可维持长达12周。

版权所有©2019美国微生物学会。

PMID：
    31712213
DOI：
    10.1128 / AAC.01701-19

newchinabok

十年之内治愈乙肝，有希望