Development of inhibitors targeting enzymatic activity of SARS-CoV-2 proteases

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07050
• 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: Chiba University
• Principal Investigator: Tyuji Hoshino 千葉大学, 大学院薬学研究院, 准教授 (90257220)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 抗ウイルス薬 / 計算機スクリーニング / Ｘ線結晶構造解析 / 薬物有機合成 / 阻害活性

Outline of Final Research Achievements

In order to create an effective antiviral drug for SARS-CoV-2, we carried out a study combining theoretical calculations, X-ray crystallography, organic synthesis, and biochemical experiments. An original software, Orientation, was used for the optimization molecular mechanics calculation. We selected the compounds expected to be effective against three target proteins, 3CL protease, PL protease, and polymerase, by computer analysis. Then, we purchased them for experimental assay. 3CL protease and PL protease were expressed and purified as recombinant proteins. The purified enzymes were used to determine the protease inhibitory activity. Five compounds showed clear inhibitory effects from in vitro measurements. Three compounds showed inhibitory activity against both 3CL protease and PL protease. The predicted binding structures were examined on the five identified chemicals in terms of the interaction with the protease catalytic site.

Free Research Field

薬物探索設計

Academic Significance and Societal Importance of the Research Achievements

SARS-CoV-2増殖阻害薬の開発については、多くの研究が行われ、新型コロナウイルス感染症治療薬の一つとして、ウイルスの3CLプロテアーゼを阻害するエンシトレルビルが承認されている。ウイルスのPLプロテアーゼについても阻害薬の探索研究が行われているが、研究報告例は少ない。感染治療においては、変異ウイルスへの対処に向けて作用機序の異なる複数の薬物の準備が必要であり、PLプロテアーゼを標的とした薬物開発は重要である。今回、PLプロテアーゼを阻害する薬物を見出せたことに意義がある。