1. Academic Validation
  2. A prodrug of the capsid assembly modulator improved druggability and lowing HBsAg and HBeAg for the treatment of chronic hepatitis B

A prodrug of the capsid assembly modulator improved druggability and lowing HBsAg and HBeAg for the treatment of chronic hepatitis B

  • Eur J Med Chem. 2023 Sep 5;257:115485. doi: 10.1016/j.ejmech.2023.115485.
Wuhong Chen 1 Ying Gong 2 Guozhang Long 3 Xinran Wang 4 Yurong Yang 5 Jia Liu 6 Heng Li 2 Xiankun Tong 7 Qiliang Zhao 3 Li Yang 8 Jianping Zuo 9 Youhong Hu 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China.
  • 2 Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
  • 4 Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China; School of Chinese Materia Medica, College of Pharmacy, Nanjing University of Chinese Medicine, No. 138 Xianlin Road, Nanjing, 210023, China.
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China; School of Chinese Materia Medica, College of Pharmacy, Nanjing University of Chinese Medicine, No. 138 Xianlin Road, Nanjing, 210023, China.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1st Xiangshan Branch Alley, Hangzhou, 310024, China.
  • 7 Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China.
  • 8 Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China. Electronic address: yangli@simm.ac.cn.
  • 9 Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China; School of Chinese Materia Medica, College of Pharmacy, Nanjing University of Chinese Medicine, No. 138 Xianlin Road, Nanjing, 210023, China. Electronic address: jpzuo@simm.ac.cn.
  • 10 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-ChongZhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1st Xiangshan Branch Alley, Hangzhou, 310024, China. Electronic address: yhhu@simm.ac.cn.
Abstract

CAMs were disclosed to alter cccDNA levels with sustained hepatitis B surface antigen (HBsAg) loss or seroconversion in preclinical investigation. Here, we report the discovery of a prodrug Yhhu6669 as CAMs based on the intestinal peptide transporter. This compound exhibited the promising anti-HBV activity with sustained suppression of HBV DNA, as well as HBsAg and HBeAg in the AAV HBV mouse model by oral treatment for 7 weeks and maintained for a further 8 weeks following drug withdraw. Our results show an alternative possibility for a functional cure by specific CAMs and provide the basis for the further mechanism study.

Keywords

Capsid assembly modulators; HBV; Hepatitis B surface antigen; Prodrug.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-149357
    HBV Inhibitor
    HBV