期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 298, 期 7, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.jbc.2022.102097
关键词
-
资金
- Program on the Innovative Development and the Application of New Drugs for Hepatitis B from the Japan Agency for Medical Research and Development (AMED) [21fk0310110T0005]
- Japan Agency for Medical Research and Development, Japan
This study used an in vitro virus method to screen and identify an antibody and a peptide for potential use in HBV treatment. A fusion protein was constructed to deliver the peptide into hepatocytes, and the experimental results showed that this fusion protein effectively suppressed the proliferation of HBV in cells.
Hepatitis B virus (HBV) infection is a major global health problem with no established cure. Dedicator of cytokinesis 11 (DOCK11), known as a guanine nucleotide exchange factor (GEF) for Cdc42, is reported to be essential for the maintenance of HBV. However, potential therapeutic strategies targeting DOCK11 have not yet been explored. We have previously developed an in vitro virus method as a more efficient tool for the analysis of proteomics and evolutionary protein engineering. In this study, using the in vitro virus method, we screened and identified a novel antiasialoglycoprotein receptor (ASGR) antibody, ASGR3-10M, and a DOCK11-binding peptide, DCS8-42A, for potential use in HBV infection. We further constructed a fusion protein (10M-D42AN) consisting of ASGR3-10M, DCS8-42A, a fusogenic peptide, and a nuclear localization signal to deliver the peptide inside hepatocytes. We show using immunofluorescence staining that 10M-D42AN was endocytosed into early endosomes and released into the cytoplasm and nucleus. Since DCS8-42A shares homology with activated cdc42-associated kinase 1 (Ack1), which promotes EGFR endocytosis required for HBV infection, we also found that 10M-D42AN inhibited endocytosis of EGFR and Ack1. Furthermore, we show 10MD42AN suppressed the function of DOCK11 in the host DNA repair system required for covalently closed circular DNA synthesis and suppressed HBV proliferation in mice. In conclusion, this study realizes a novel hepatocyte-specific drug delivery system using an anti-ASGR antibody, a fusogenic peptide, and DOCK11-binding peptide to provide a novel treatment for HBV.
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