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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
PMID: 37229833 DOI: 10.1016/j.ejmech.2023.115485
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.
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