Generation of a high-affinity anti-myonecrosis factor Fab for the development of a therapeutic agent for Protobothrops flavoviridis bite.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15249
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47020:Pharmaceutical analytical chemistry and physicochemistry-related
• Research Institution: Sojo University
• Principal Investigator: Nakamura Hitomi 崇城大学, 薬学部, 講師 (60510691)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: Fab / 安定性 / 結合親和性 / フレームワーク領域 / ハブ咬傷

Outline of Final Research Achievements

Myonecrosis induced by BPII, the myotoxin of Protobothrops flavoviridis venom, causes severe local tissue damage. Therefore, there is a need for a therapeutic agent that is more effective than antivenom in inhibiting myonecrosis. However, the details of the mechanism by which BPII induces myonecrosis remain unclear, which is one of the factors hindering the development of myonecrosis inhibitors. The purpose of this study was to improve the structural stability and binding affinity of anti-BPII Fab to generate a useful tool for elucidating the mechanism of BPII-induced myonecrosis. We found that the I11L and T84L mutations introduced into the heavy chain variable region of anti-BPII Fab improved the binding affinity and the structural stability, respectively. We produced the improved anti-BPII Fab by introducing these two mutations.

Free Research Field

蛋白質工学

Academic Significance and Societal Importance of the Research Achievements

BPIIの筋壊死誘導メカニズムが明らかになっていないことが、筋壊死抑制効果の高い治療薬開発の妨げとなってきた。本研究課題で改良型抗BPII Fabを作製したことで、これとBPIIの複合体の構造解析を行い、BPIIの筋壊死誘導に関する詳細な構造情報を得ることが可能となった。この情報は、BPIIの筋壊死誘導メカニズムの解明につながると同時に、構造情報を基にした創薬にも応用可能である。これらが、ハブ咬傷被害の後遺症によるQOL低下の防止につながることが期待される。