A novel hepatitis B virus capsid assembly modulator QL-007 inhibits HBV replication and infection through altering capsid assembly

Xi，Jingyuan1,2; Gu，Zhiqiang1; Sun，Chunyan3; Chen，Zimin4; Zhang，Ting1; Chen，Ran1,5; Liu，Tianyu6; Liao，Hao1,7; Zou，Jun1; Yang，Danli1; Xu，Qiang1; Wang，Jie1; Wei，Guochao1; Cheng，Zhe3; Lu，Fengmin1,8; Chen，Xiangmei1

2023-10-01

10.1016/j.antiviral.2023.105715

Antiviral Research   Impact Factor & Quartile

0166-3542

1872-9096

The core protein allosteric modulators (CpAMs) have shown great potential as highly effective antiviral drugs against hepatitis B virus (HBV) in preclinical studies and clinical trials. In this study, we evaluated a small molecule compound called QL-007, which could potentially influence capsid assembly, using HBV replicated and susceptible cell models as well as mice infected with rAAV-HBV. QL-007 significantly inhibited HBV replication in a dose-dependent manner both in vitro and in vivo, resulting in significant decreases in HBV DNA, 3.5 kb HBV RNA and HBeAg. Furthermore, QL-007 not only induced the formation of misshaped Cp149 capsids but also possessed the capability to disassemble HBV capsids. It is noteworthy that QL-007 effectively reduced cccDNA biosynthesis in de novo infections. Mechanistically, QL-007 blocked the encapsidation of pgRNA and induced aberrant polymers assembly at concentrations ≥100 nM, while having no impact on the stability of core proteins. In conclusion, our findings underscore the potential of QL-007 as an effective agent against HBV replication and introduce it as a novel CpAM for the antiviral treatment of chronic hepatitis B.

Antiviral Capsid assembly Core protein allosteric modulator Hepatitis B virus QL-007

English

Others

Natural Science Foundation of Beijing Municipality[7212063];Natural Science Foundation of Beijing Municipality[7222108];National Natural Science Foundation of China[82072280];National Natural Science Foundation of China[82272315];

PHARMACOLOGY & TOXICOLOGY

2-s2.0-85171152555

Scopus

1.Department of Microbiology & Infectious Disease Center,School of Basic Medical Sciences,Peking University Health Science Center,Beijing,100191,China
2.Department of Clinical Laboratory Center,Beijing Children's Hospital,Capital Medical University,National Center for Children's Health,Beijing,100045,China
3.Department of Nonclinical Development,Qilu Pharmaceutical Co,Ltd,Jinan,243 Gong Ye Bei Road, Shandong,250100,China
4.R&D Department,Xiamen Innobiomax Biotechnology Co,Ltd,Xiamen,126 Xin Yuan Road, Fujian,361022,China
5.Institute of Human Virology,Key Laboratory of Tropical Disease Control of Ministry of Education,Zhongshan School of Medicine,Sun Yat-sen University,Guangzhou,Guangdong,510080,China
6.Medical Isotopes Research Center,Department of Radiation Medicine,School of Basic Medical Sciences,Peking University Health Science Center,Beijing,100191,China
7.Department of Clinical Laboratory,Shenzhen Third People's Hospital,Southern University of Science and Technology,National Clinical Research Center for Infectious Diseases,Shenzhen,518112,China
8.Peking University Hepatology Institute,Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases,Peking University People's Hospital,Beijing,100044,China

Xi，Jingyuan,Gu，Zhiqiang,Sun，Chunyan,et al. A novel hepatitis B virus capsid assembly modulator QL-007 inhibits HBV replication and infection through altering capsid assembly[J]. Antiviral Research,2023,218.

Xi，Jingyuan.,Gu，Zhiqiang.,Sun，Chunyan.,Chen，Zimin.,Zhang，Ting.,...&Chen，Xiangmei.(2023).A novel hepatitis B virus capsid assembly modulator QL-007 inhibits HBV replication and infection through altering capsid assembly.Antiviral Research,218.

Xi，Jingyuan,et al."A novel hepatitis B virus capsid assembly modulator QL-007 inhibits HBV replication and infection through altering capsid assembly".Antiviral Research 218(2023).