2. Academic Validation
  3. Discovery of Novel cccDNA Reducers toward the Cure of Hepatitis B Virus Infection

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

  • J Med Chem. 2022 Aug 25;65(16):10938-10955. doi: 10.1021/acs.jmedchem.1c02215.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-151134
    HBV cccDNA Reducer
    HBV