OP-01一种新型吡唑HBV核衣壳形成抑制剂 表现出对抗HBV变异体

StephenW

OP-01 A novel pyrazole HBV nucleocapsid formation inhibitor
demonstrating high activity against HBV variants that are resistant
to class I and class II core protein allosteric modulators
Zhijun Zhang1, Bo Liang2, Bo Hua2, Qiu Jin2, Huanming Chen2
1ZhiMeng Biopharma, RandD, Shanghai, China; 1ZhiMeng Biopharma, RandD, Shanghai, China
Email: [email protected]
Background and aims: Current drugs for chronic hepatitis B (NAs and IFN) rarely provide a cure for
patients. New classes of drugs that hit different virus targets are welcomed to bring a higher cure rate
in finite treatment periods. We have discovered a novel series of pyrazole compounds as HBV
nucleocapsid formation inhibitors (represented by CB-HBV-001). CB-HBV-001 is structurally distinctive
from the current class I (heteroaryldihydropyrimidines, e.g., BAY-41-4109 and GLS4) and class II
(phenylpropenamides and sulfamoylbenzamides, e.g., AT-130 and NVR3-778) HBV core protein
allosteric modulators (CpAMs). We evaluated the antiviral activities of CB-HBV-001, class I, and class
II compounds against a panel of viruses containing different mutations in HBV core protein including the
core T109I mutant that has shown resistance to both NV-010-001 and BAY 41-4109 core protein
modulators (Klumpp et al., PNAS 2015).
Method: Virus infection of PHH and Southern Blot analysis were used to quantify the HBV cccDNA.
HepG2 cells were transfected with 1.3x HBV DNA carrying different core mutations. Newly synthesized
virus DNA was quantified by PCR.
Results: CB-HBV-001 accelerated the formation of capsid devoid of HBV pgRNA and DNA in a dosedependent
manner. When added at the time of virus infection of PHH, CB-HBV-001 inhibited HBV
cccDNA formation and HBsAg level. In addition, when used in combination with IFN-alpha in PHH assay,
CB-HBV-001 demonstrated an additive effect in inhibiting both HBsAg and DNA, while it only showed
an additive inhibitory effect with Tenofovir on HBV DNA. Most importantly, CB-HBV-001 was highly
active against a panel of viruses that contain mutations in core protein and that are resistant to classes
I and II CpAMs.
Conclusion: The unique structure of CB-HBV-001 and its distinctive antiviral profile against core protein
mutants distinguish itself from reported class I and class II HBV CpAMs. These characteristics of CBHBV-
001 warrant its clinic evaluation for treatment of chronic HBV infection.
Figure:
Class I NA
CB-HBV-001
Compound 2
(WO2017/181141)
AT-130 GLS4 ETV
F23Y 189 (6.1) 453 (12) 7573 (37) 38 (3.5) 2.7 (1.0)
L30F 59 (1.9) 228 (5.9) 1289 (6.3) 56 (5.1) 2.8 (1.0)
I105F 5.7 (0.2) 491 (13) 631 (3.1) 44 (4.0) 3.4 (1.2)
T33Q 159 (5.1) >10000 (>257) >10000 (>49) 428 (39) 2.8 (1.0)
T109I 23 (0.8) 10 (0.3) 81 (0.4) 134 (12.3) 1.4 (0.5)
U95551(wild type) 31 (1.0) 39 (1.0) 206 (1.0) 11 (1.0) 2.8 (1.0)

StephenW

OP-01一种新型吡唑HBV核衣壳形成抑制剂
表现出对抗HBV变异体的高活性
I类和II类核心蛋白质变构调节剂
张志军1，梁亮2，博华2，邱金2，陈焕明2
1ZhiMeng Biopharma，RandD，中国上海; 1ZhiMeng Biopharma，RandD，中国上海
电子邮件：[email protected]
背景和目的：目前用于慢性乙型肝炎（NAs和IFNα）的药物很少能提供治疗方法
耐心。欢迎达到不同病毒目标的新类药物带来更高的治愈率
在有限的治疗期间。我们发现了一系列新的吡唑化合物如HBV
核衣壳形成抑制剂（由CB-HBV-001代表）。 CB-HBV-001结构独特
来自目前的I类（杂芳基二氢嘧啶，例如BAY-41-4109和GLS4）和II类
（苯基丙烯酰胺和氨磺酰苯甲酰胺，例如AT-130和NVR3-778）HBV核心蛋白
变构调节剂（CpAM）。我们评估了CB-HBV-001，I类和类的抗病毒活性
II化合物针对一组含有HBV核心蛋白不同突变的病毒，包括
核心T109I突变体已显示出对NV-010-001和BAY 41-4109核心蛋白的抗性
调节剂（Klumpp等，PNAS 2015）。
方法：用PHH病毒感染和Southern Blot分析定量检测HBV cccDNA。
用携带不同核心突变的1.3x HBV DNA转染HepG2细胞。新合成
通过PCR定量病毒DNA。
结果：CB-HBV-001以剂量依赖性加速缺乏HBV pgRNA和DNA的衣壳形成
方式。当病毒感染PHH时加入，CB-HBV-001抑制HBV
cccDNA形成和HBsAg水平。此外，当在PHH测定中与IFN-α联合使用时，
CB-HBV-001在抑制HBsAg和DNA方面表现出加成效应，但仅表现出来
替诺福韦对HBV DNA的抑制作用。最重要的是，CB-HBV-001是高度的
对含有核心蛋白突变且对类具有抗性的一组病毒起作用
I和II CpAMs。
结论：CB-HBV-001的独特结构及其对核心蛋白的独特抗病毒谱
突变体区别于报道的I类和II类HBV CpAM。 CBHBV的这些特征 -
001保证其治疗慢性HBV感染的临床评估。
数字：
I级NA
CB-HBV-001
化合物2
（WO2017 / 181141）
AT-130 GLS4 ETV
F23Y 189（6.1）453（12）7573（37）38（3.5）2.7（1.0）
L30F 59（1.9）228（5.9）1289（6.3）56（5.1）2.8（1.0）
I105F 5.7（0.2）491（13）631（3.1）44（4.0）3.4（1.2）
T33Q 159（5.1）> 10000（> 257）> 10000（> 49）428（39）2.8（1.0）
T109I 23（0.8）10（0.3）81（0.4）134（12.3）1.4（0.5）
U95551（野生型）31（1.0）39（1.0）206（1.0）11（1.0）2