Comparative structural analysis of reverse transcriptase of HIV and HBV for development of anti-HBV agents

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07522
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49060:Virology-related
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Hattori Shinichiro 国立研究開発法人国立国際医療研究センター, その他部局等, 上級研究員 (60709484)
• Co-Investigator(Kenkyū-buntansha): 安武 義晃 国立研究開発法人産業技術総合研究所, 生命工学領域, 主任研究員 (20415756)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 逆転写酵素 / HBV / HIV / 核酸アナログ

Outline of Final Research Achievements

Structural studies of HBV reverse transcriptase (RT) have made no progress due to its significant insolubility. In this study, we constructed RT chimeras by introducing amino acids from HBV RT into the HIV RT, and furthermore, by introducing known drug-resistant mutations, we investigated the drug resistance mechanism structurally and virologically. Mutations of the anti-HBV drug entecavir (ETV) was shown to change the shape of the binding site of ETV and cause steric hindrance. This suggests that the steric hindrance attenuates ETV binding and reduces its susceptibility. The structural information obtained in this study and the correlation with drug susceptibility are expected to contribute to the design and development of new nucleic acid analogs that exhibit activity against resistant mutant strains.

Free Research Field

ウイルス学

Academic Significance and Societal Importance of the Research Achievements

本研究は、未だ成し遂げられていないHBV RTの結晶構造解析を、キメラRTを用いることで実際の結晶を取得し、詳細な構造解析を可能とし、HBV RTの構造学的特徴をより詳細かつ明確に理解でき、さらなる知見を蓄積できる。さらにウイルス学的・酵素学的解析を加味することで、生物学的な特性を詳細かつ総合的に検討できるようになる。これは薬剤の活性発揮機序やウイルスの耐性獲得機序の解明につながり、より強力かつ耐性獲得を許さない新規抗HBV薬の開発に応用・貢献すると期待できる。