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标题: 发现治疗乙型肝炎病毒感染的新型 cccDNA 还原剂 [打印本页]

作者: StephenW 时间: 2022-8-19 18:21 标题: 发现治疗乙型肝炎病毒感染的新型 cccDNA 还原剂

发现治疗乙型肝炎病毒感染的新型 cccDNA 还原剂
陈东东 1 , 谭雪飞 1 , 陈文明 1 , 刘永福 1 , 李超 1 , 吴军 1 , 郑家敏 1 , 沉洪 C 1 , 张美芳 2 , 吴伟光 2 , 王林 3 , 景雄 3 , 洁玉戴 4 , 孙开 4 , 张继涛 5 , 昆仑翔 6 , 李宝村 6 , 倪小菊 6 , 朱启辉 6 , 鲁高 6 , 王立 6 , 宋峰 1
隶属关系
隶属关系

1
中国上海市李时镇路371号5号楼罗氏制药研究与早期开发部，罗氏上海创新中心药物化学部，邮编：201203。
2
Lead Discovery，罗氏上海创新中心，罗氏制药研究与早期开发部，中国上海市李时镇路 371 号 5 号楼，邮编 201203。
3
pCMC，罗氏上海创新中心，罗氏制药研究与早期开发，中国上海市李时镇路 371 号 5 号楼 201203。
4
药学部，罗氏上海创新中心，罗氏制药研究与早期开发部，中国上海市李时镇路 371 号 5 号楼，邮编 201203。
5
制药科学，罗氏巴塞尔创新中心，罗氏制药研究与早期开发，Grenzacherstrasse 124，巴塞尔 CH-4070，瑞士。
6
Discovery Virology, 罗氏上海创新中心，罗氏制药研究与早期开发部，中国上海市李时镇路 371 号 5 号楼 201203。

PMID：35973101 DOI：10.1021/acs.jmedchem.1c02215

抽象的

慢性乙型肝炎病毒 (HBV) 感染是一种全球性疾病，每年导致数千人死亡。目前，由于人类无法消除共价闭合环状 DNA (cccDNA)，因此没有可以完全治愈已感染 HBV 患者的治疗方法，即使在长时间的病毒抑制后，它仍可作为（重新）引发感染的模板。通过表型筛选，我们发现黄酮系列作为新型 HBV cccDNA 减少剂，随后的结构优化导致鉴定出具有改善的抗病毒活性和药代动力学特征的先导化合物。代表性化合物 59 表现出良好的效力和口服生物利用度，没有细胞毒性。在 HBVcircle 小鼠模型中，化合物 59 在显着降低 HBV 抗原、DNA 和肝内 cccDNA 水平方面表现出优异的功效。

作者: StephenW 时间: 2022-8-19 18:22

Discovery of Novel cccDNA Reducers toward the Cure of Hepatitis B Virus Infection
Dongdong Chen 1 , Xuefei Tan 1 , Wenming Chen 1 , Yongfu Liu 1 , Chao Li 1 , Jun Wu 1 , Jiamin Zheng 1 , Hong C Shen 1 , Meifang Zhang 2 , Waikwong Wu 2 , Lin Wang 3 , Jing Xiong 3 , Jieyu Dai 4 , Kai Sun 4 , Jitao David Zhang 5 , Kunlun Xiang 6 , Baocun Li 6 , XiaoJu Ni 6 , Qihui Zhu 6 , Lu Gao 6 , Li Wang 6 , Song Feng 1
Affiliations
Affiliations

1
Department of Medicinal Chemistry, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China.
2
Lead Discovery, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China.
3
pCMC, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China.
4
Pharmaceutical Sciences, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China.
5
Pharmaceutical Science, Roche Innovation Center Basel, Roche Pharma Research & Early Development, Grenzacherstrasse 124, Basel CH-4070, Switzerland.
6
Discovery Virology, Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Building 5, No. 371, Lishizhen Road, Shanghai 201203, China.

PMID: 35973101 DOI: 10.1021/acs.jmedchem.1c02215

Abstract

Chronic hepatitis B virus (HBV) infection is a worldwide disease that causes thousands of deaths per year. Currently, there is no therapeutic that can completely cure already infected HBV patients due to the inability of humans to eliminate covalently closed circular DNA (cccDNA), which serves as the template to (re)initiate an infection even after prolonged viral suppression. Through phenotypic screening, we discovered xanthone series hits as novel HBV cccDNA reducers, and subsequent structure optimization led to the identification of a lead compound with improved antiviral activity and pharmacokinetic profiles. A representative compound 59 demonstrated good potency and oral bioavailability with no cellular toxicity. In an HBVcircle mouse model, compound 59 showed excellent efficacy in significantly reducing HBV antigens, DNA, and intrahepatic cccDNA levels.

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