Structural basis for the hepatocyte specific entry and replication mechanisms of hapatitis B virus and structural based drug discovery

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06494
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47020:Pharmaceutical analytical chemistry and physicochemistry-related
• Research Institution: Keio University
• Principal Investigator: Yokogawa Mariko 慶應義塾大学, 薬学部(芝共立), 講師 (60648020)
• Co-Investigator(Kenkyū-buntansha): 大澤 匡範 慶應義塾大学, 薬学部(芝共立), 教授 (60361606)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: B型肝炎ウイルス / タンパク質―タンパク質相互作用 / NMR / 等温滴定型カロリメトリー

Outline of Final Research Achievements

Hepatitis B virus enters hepatocyte via the interaction between preS1 region of the envelope protein called large surface protein and NTCP: an HBV receptor specifically expressed in hepatocyte. OHBF-C is a compound that is reported to bind to preS1 and inhibit the HBV infection. In this study, we analyzed the interaction between preS1 and OHBF-C in order to reveal the inhibitory mechanism by OHBF-C.
Isothermal titration calorimetry, NMR, and co-precipitation assay results suggested that OHBF-C and preS1 forms multivalent interaction to aggregate, which lead to the inhibition of the HBV infection.

Free Research Field

構造生物学

Academic Significance and Societal Importance of the Research Achievements

本研究において、HBVの外殻膜上の表面抗原タンパク質LのpreS1領域に直接結合し、HBVの感染を阻害する活性を有することが報告されているOHBF-Cの作用機序に関する知見を得た。本研究において明らかにしたpreS1に直接結合するOHBF-Cの結合様式は、単独では特定の立体構造を形成しないために立体構造に基づく分子設計が困難と考えられるpreS1を標的とする高活性な阻害化合物の創製に有用な情報を与える