Development of a versatile design method for protease inhibitors based on hydroxyproline

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K06953
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: Kyoto Pharmaceutical University
• Principal Investigator: Kobayashi Kazuya 京都薬科大学, 薬学部, 准教授 (80647868)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: プロテアーゼ阻害剤 / ヒドロキシプロリン / BACE1 / SARS 3CLプロテアーゼ

Outline of Final Research Achievements

To establish a universal strategy for the design of protease inhibitors, I have investigated the development of inhibitors against β-secretase (BACE1) and SARS (severe acute respiratory syndrome) 3CL protease (3CLpro), which are therapeutic targets for Alzheimer's disease and SARS, respectively, using hydroxyproline as a common backbone. In the case of the BACE1 inhibitors, we have obtained valuable structure-activity relationship information for a novel skeleton-based inhibitor. This information will be useful in developing highly active derivatives in the future. As for the SARS 3CLpro inhibitors, we have identified a new inhibitor with single digit μM (IC50) activity from the design based on the common backbone.

Free Research Field

創薬科学

Academic Significance and Societal Importance of the Research Achievements

全く異なる2つのプロテアーゼを標的とした阻害剤の開発研究を、共通の基本骨格に基づく設計戦略に従って実施し、一定の阻害活性を有する誘導体を見出すことができたことから、本研究成果はプロテアーゼを対象とする創薬研究における新たな設計手法を示すことができたと考えている。プロテアーゼ阻害剤の新たな設計手法の確立は、医薬品開発研究をより飛躍させるために必要な物であり、本成果はその一助になりうるものと考える。