2. Academic Validation
  3. A novel phthalazinone derivative as a capsid assembly modulator inhibits hepatitis B virus expression

A novel phthalazinone derivative as a capsid assembly modulator inhibits hepatitis B virus expression

  • Antiviral Res. 2023 Nov 25:221:105763. doi: 10.1016/j.antiviral.2023.105763.
Li Yang 1,  Ying Gong 2,  Feifei Liu 3,  Wuhong Chen 4,  Xinran Wang 5,  Guozhang Long 4,  Heng Li 2,  Fuling Xiao 2,  MengJi Lu 6,  Youhong Hu 7,  Xiankun Tong 8,  Jianping Zuo 9
Affiliations

Affiliations

  • 1 Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China; Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 200000,China.
  • 2 Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
  • 3 Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China.
  • 5 Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, No.138 Xianlin Road, Nanjing, 210023, China.
  • 6 Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, 45122, Germany.
  • 7 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China. Electronic address: yhhu@simm.ac.cn.
  • 8 Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. Electronic address: xktong@simm.ac.cn.
  • 9 Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, No.138 Xianlin Road, Nanjing, 210023, China. Electronic address: jpzuo@simm.ac.cn.
PMID: 38008192 DOI: 10.1016/j.antiviral.2023.105763
Abstract

Development of new anti-hepatitis B virus (HBV) drugs that target viral capsid assembly is a very active research field. We identify a novel phthalazinone derivative, compound 5832, as a potent HBV inhibitor. In this study, we intend to elaborate the Antiviral effect and mechanism of 5832 against HBV in vitro and in vivo. Compound 5832 treatment induces the formation of genome-free empty capsid by interfering with the core protein assembly domain, which significantly decreases the extracellular and intracellular HBV DNA. In the AAV-HBV transduced mouse model, 5832 suppresses serum HBV DNA after 4-week treatment, and decreases HBsAg and HBeAg levels. 5832 treatment also reduces intrahepatic HBV RNA, DNA and HBcAg levels. During the follow-up period after treatment withdrawal, serum antigen levels demonstrated no increase. We demonstrate 5832 treatment could active apoptotic signaling by elevating the expression of Death Receptor 5 (DR5), which participated in corresponding HBcAg-positive hepatocyte eradication. Phthalazinone derivative 5832 may serve as a promising anti-HBV drug candidate to improve the treatment options for chronic HBV Infection.

Keywords

Apoptosis; Capsid assembly; Hepatitis B virus; Phthalazinone derivatives.

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