Discovery of Novel cccDNA Reducers toward the Cure of Hepatitis B Virus Infection

被引：11

作者：

Chen, Dongdong ^{[1
]}

Tan, Xuefei ^{[1
]}

Chen, Wenming ^{[1
]}

Liu, Yongfu ^{[1
]}

Li, Chao ^{[1
]}

Wu, Jun ^{[1
]}

Zheng, Jiamin ^{[1
]}

Shen, Hong C. ^{[1
]}

Zhang, Meifang ^{[2
]}

Wu, Waikwong ^{[2
]}

Wang, Lin ^{[3
]}

Xiong, Jing ^{[3
]}

Dai, Jieyu ^{[4
]}

Sun, Kai ^{[4
]}

Zhang, Jitao David ^{[4
]}

Xiang, Kunlun ^{[5
]}

Li, Baocun ^{[5
]}

Ni, XiaoJu ^{[5
]}

Zhu, Qihui ^{[5
]}

Gao, Lu ^{[5
]}

Wang, Li ^{[5
]}

Feng, Song ^{[1
]}

机构：

[1] Roche Innovat Ctr Shanghai, Dept Med Chem, Roche Pharm Res & Early Dev, Shanghai 201203, Peoples R China

[2] Roche Innovat Ctr Shanghai, Roche Pharm Res & Early Dev, Shanghai 201203, Peoples R China

[3] Roche Innovat Ctr Shanghai, PCMC, Roche Pharm Res & Early Dev, Shanghai 201203, Peoples R China

[4] Roche Innovat Ctr Shanghai, Pharmaceut Sci, Roche Pharm Res & Early Dev, Shanghai 201203, Peoples R China

[5] Roche Innovat Ctr Shanghai, Discovery Virol, Roche Pharm Res & Early Dev, Shanghai 201203, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 65卷 / 16期

关键词：

HEPATOMA-CELL LINE; CIRCULAR DNA; GENOME; PARTICLES; TOOL;

D O I：

10.1021/acs.jmedchem.1c02215

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：10938 / 10955

页数：18

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