NVR 3-778的临床前特征，这是一种针对乙型肝炎病毒的一流​

StephenW

Antimicrob Agents Chemother. 2018 Oct 29. pii: AAC.01734-18. doi: 10.1128/AAC.01734-18. [Epub ahead of print]
Preclinical Characterization of NVR 3-778, a First-in-Class Capsid Assembly Modulator Against the Hepatitis B Virus.
Lam AM1, Espiritu C2, Vogel R2, Ren S2, Lau V2, Kelly M2, Kuduk SD2, Hartman GD2, Flores OA2, Klumpp K2.
Author information

1
    Novira Therapeutics Inc, part of the Janssen Pharmaceutical companies, 1400 McKean Road, Spring House, PA 19477, USA [email protected].
2
    Novira Therapeutics Inc, part of the Janssen Pharmaceutical companies, 1400 McKean Road, Spring House, PA 19477, USA.

Abstract

NVR 3-778 is the first Capsid Assembly Modulator (CAM) that has demonstrated antiviral activity in HBV infected patients. NVR 3-778 inhibited the generation of infectious HBV DNA containing virus particles with a mean antiviral EC50 of 0.40 µM in HepG2.2.15 cells. The antiviral profile of NVR 3-778 indicates pan-genotypic antiviral activity and lack of cross-resistance with nucleos(t)ide inhibitors of HBV replication. The combination of NVR 3-778 with nucleos(t)ide analogs in vitro resulted in additive or synergistic antiviral activity. Mutations within the hydrophobic pocket at the dimer-dimer interface of the core protein could confer resistance to NVR 3-778, which is consistent with the ability of the compound to bind to core and to induce capsid assembly. By targeting core, NVR 3-778 inhibits pgRNA encapsidation, viral replication and the production of HBV DNA- and HBV RNA-containing particles. NVR 3-778 also inhibited de novo infection and viral replication in primary human hepatocytes with EC50 values of 0.81 µM against HBV DNA and between 3.7 to 4.8 µM against the production of HBV antigens and intracellular HBV RNA. NVR 3-778 showed favorable pharmacokinetics and safety in animal species, allowing serum levels in excess of 100 µM to be achievable in mice and thus enabling efficacy studies in vivo The overall preclinical profile of NVR 3-778 predicted antiviral activity in vivo and supported further evaluation for safety, pharmacokinetics, and antiviral activity in HBV infected patients.

PMID:
    30373799
DOI:
    10.1128/AAC.01734-18

StephenW

抗微生物剂Chemother。 2018年10月29日.pii：AAC.01734-18。 doi：10.1128 / AAC.01734-18。 [提前打印]
NVR 3-778的临床前特征，这是一种针对乙型肝炎病毒的一流​​衣壳组装调节剂。
Lam AM1，Espiritu C2，Vogel R2，Ren S2，Lau V2，Kelly M2，Kuduk SD2，Hartman GD2，Flores OA2，Klumpp K2。
作者信息

1
    Novira Therapeutics Inc，Janssen Pharmaceutical公司的一部分，1400 McKean Road，Spring House，PA 19477，USA [email protected]。
2
    Novira Therapeutics Inc，Janssen Pharmaceutical公司的一部分，1400 McKean Road，Spring House，PA 19477，USA。

抽象

NVR 3-778是第一个在HBV感染患者中表现出抗病毒活性的衣壳装配调节剂（CAM）。 NVR 3-778抑制含有病毒颗粒的感染性HBV DNA的产生，其在HepG2.2.15细胞中的平均抗病毒EC50为0.40μM。 NVR 3-778的抗病毒特征表明泛基因型抗病毒活性和缺乏与HBV复制的核苷（酸）抑制剂的交叉抗性。 NVR 3-778与核苷（t）ide类似物的体外组合产生了加和或协同的抗病毒活性。在核心蛋白的二聚体 - 二聚体界面处的疏水口袋内的突变可赋予对NVR 3-778的抗性，这与化合物结合核心和诱导衣壳组装的能力一致。通过靶向核心，NVR 3-778抑制pgRNA衣壳化，病毒复制和含HBV DNA和HBV RNA的颗粒的产生。 NVR 3-778还抑制原代人肝细胞中的新生感染和病毒复制，对HBV DNA的EC50值为0.81μM，对HBV抗原和细胞内HBV RNA的产生为3.7-4.8μM。 NVR 3-778在动物物种中显示出良好的药代动力学和安全性，允许在小鼠中实现超过100μM的血清水平，从而实现体内功效研究.NVR 3-778的整体临床前特征预测体内抗病毒活性并进一步支持评估HBV感染患者的安全性，药代动力学和抗病毒活性。

结论：
    30373799
DOI：
    10.1128 / AAC.01734-18

齐欢畅

不错。

newchinabok

nvr3—778已处于淘汰货

灵魂不屈

感谢分享。