GLP-26作为有效的乙型肝炎病毒衣壳装配调节剂的功效，潜在

StephenW

Studies on the Efficacy, Potential Cardiotoxicity and Monkey Pharmacokinetics of GLP-26 as a Potent Hepatitis B Virus Capsid Assembly Modulator
Selwyn J Hurwitz  1 , Noreen McBrearty  2 , Alla Arzumanyan  2 , Eugene Bichenkov  2 , Sijia Tao  1 , Leda Bassit  1 , Zhe Chen  1 , James J Kohler  1 , Franck Amblard  1 , Mark A Feitelson  2 , Raymond F Schinazi  1
Affiliations
Affiliations

    1
    Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, 1760 Haygood Drive, Atlanta, GA 30322, USA.
    2
    Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA.

    PMID: 33467678 DOI: 10.3390/v13010114

Abstract

While treatment options are available for hepatitis B virus (HBV), there is currently no cure. Anti-HBV nucleoside analogs and interferon-alpha 2b rarely clear HBV covalently closed circular DNA (cccDNA), requiring lifelong treatment. Recently, we identified GLP-26, a glyoxamide derivative which modulates HBV capsid assembly. The impact of GLP-26 on viral replication and integrated DNA was assessed in an HBV nude mouse model bearing HBV transfected AD38 xenografts. At day 45 post-infection, GLP-26 reduced HBV titers by 2.3-3 log10 versus infected placebo-treated mice. Combination therapy with GLP-26 and entecavir reduced HBV log10 titers by 4.6-fold versus placebo. Next, we examined the pharmacokinetics (PK) in cynomolgus monkeys administered GLP-26 via IV (1 mg/kg) or PO (5 mg/kg). GLP-26 was found to have 34% oral bioavailability, with a mean input time of 3.17 h. The oral dose produced a mean peak plasma concentration of 380.7 ng/mL, observed 0.67 h after administration (~30-fold > in vitro EC90 corrected for protein binding), with a mean terminal elimination half-life of 2.4 h and a mean area under the plasma concentration versus time curve of 1660 ng·hr/mL. GLP-26 was 86.7% bound in monkey plasma. Lastly, GLP-26 demonstrated a favorable toxicity profile confirmed in primary human cardiomyocytes. Thus, GLP-26 warrants further preclinical development as an add on to treatment for HBV infection.

Keywords: GLP-26; capsid effector; cardiomyocytes; cynomolgus monkeys; hepatitis B virus; mouse model; oral bioavailability; pharmacokinetics.

StephenW

GLP-26作为有效的乙型肝炎病毒衣壳装配调节剂的功效，潜在的心脏毒性和猴子药代动力学的研究
Selwyn J Hurwitz 1，Noreen McBrearty 2，Alla Arzumanyan 2，Eugene Bichenkov 2，Sijia Tao 1，Leda Bassit 1，Zhen Chen 1，James J Kohler 1，Franck Amblard 1，Mark A Feitelson 2，Raymond F Schinazi 1
隶属关系
隶属关系

    1个
    美国亚特兰大埃默里大学医学院和儿童保健科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，海地古德路1760号，美国乔治亚州30322。
    2
    坦普尔大学科学技术学院生物系，费城，宾夕法尼亚州19122，美国。

    PMID：33467678 DOI：10.3390 / v13010114

抽象

尽管可以选择治疗乙肝病毒（HBV）的方法，但目前尚无治愈方法。抗HBV核苷类似物和干扰素-α2b很少清除HBV共价闭合的环状DNA（cccDNA），需要终身治疗。最近，我们确定了GLP-26，一种乙二酰胺酰胺衍生物，可调节HBV衣壳装配。在带有HBV转染的AD38异种移植物的HBV裸鼠模型中评估了GLP-26对病毒复制和整合的DNA的影响。感染后第45天，与感染安慰剂治疗的小鼠相比，GLP-26降低了HBV滴度2.3-3 log10。与安慰剂相比，GLP-26和恩替卡韦的联合治疗使HBV log10滴度降低了4.6倍。接下来，我们检查了通过静脉注射（1 mg / kg）或口服PO（5 mg / kg）施用GLP-26的食蟹猴的药代动力学（PK）。发现GLP-26具有34％的口服生物利用度，平均输入时间为3.17小时。口服剂量产生的平均峰值血浆浓度为380.7 ng / mL，在给药后0.67小时观察到（〜30倍>体外EC90校正的蛋白质结合），平均末端消除半衰期为2.4 h，平均面积血浆浓度与时间的关系曲线为1660 ng·hr / mL。 GLP-26在猴血浆中的结合率为86.7％。最后，GLP-26在原代人心肌细胞中显示出良好的毒性。因此，作为对HBV感染治疗的补充，GLP-26值得进一步的临床前开发。

关键字：GLP-26；衣壳效应子心肌细胞食蟹猴乙型肝炎病毒;鼠标模型口服生物利用度；药代动力学。

lancas

还好，不断有新的药物~~