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

Wuhong Chen; Ying Gong; Guozhang Long; Xinran Wang; Yurong Yang; Jia Liu; Heng Li; Xiankun Tong; Qiliang Zhao; Li Yang; Jianping Zuo; Youhong Hu

doi:10.1016/j.ejmech.2023.115485

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. Epub 2023 May 13.

Authors

Wuhong Chen¹, Ying Gong², Guozhang Long³, Xinran Wang⁴, Yurong Yang⁵, Jia Liu⁶, Heng Li², Xiankun Tong⁷, Qiliang Zhao³, Li Yang⁸, Jianping Zuo⁹, Youhong Hu¹⁰

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.

MeSH terms

Animals
Antiviral Agents / pharmacology
Antiviral Agents / therapeutic use
Capsid
Capsid Proteins
DNA, Viral
Hepatitis B Surface Antigens / therapeutic use
Hepatitis B e Antigens
Hepatitis B virus / genetics
Hepatitis B, Chronic* / drug therapy
Mice
Prodrugs* / pharmacology
Prodrugs* / therapeutic use

Substances

Hepatitis B Surface Antigens
Hepatitis B e Antigens
Prodrugs
Antiviral Agents
Capsid Proteins
DNA, Viral