Strategies for transformation of a substrate-based protease inhibitor to non-peptide inhibitor

2019 Fiscal Year Final Research Report

• Project/Area Number: 16H05104
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Kyoto Pharmaceutical University
• Principal Investigator: Akaji Kenichi 京都薬科大学, 薬学部, 教授 (60142296)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: 医薬品化学 / 創薬 / プロテアーゼ / 阻害剤 / アルツハイマー病 / 新型コロナウイルス

Outline of Final Research Achievements

Two strategies were examined to transform from substrate-based protease inhibitor to non-peptide drug-like low molecular compound; the one is cyclization combined with introduction of suitable functional groups on the ring structure and the another is utilization of fused-ring structure as a novel scaffold of inhibitors. Inhibitors for BACE1, engaged in production of an amyloid beta in Alzheimer disease, and inhibitors for SARS 3CL protease, essential for proliferation of SARS corona virus, were selected for the objects.
In the design of BACE1 inhibitors, cyclization via an olefin bond combined with beta site methyl groups was found to be most effective. In the design of inhibitors for SARS 3CL protease, two new hydrophobic scaffolds, decahydroisoquinoline and octahydroisochromene, were found to be effective fused-ring structures to incorporate several functional groups interacting with the protease.

Free Research Field

薬学

Academic Significance and Societal Importance of the Research Achievements

本研究により、疎水性相互作用に基づく適度な疎水性を持った新規な阻害剤中心骨格の創製に一般的に応用可能な独創的な手法を確立できた。本研究の遂行には、プロテアーゼ・阻害剤複合体構造解析結果をオンタイムで阻害剤設計にフィードバックでき、活性評価・構造解析まで一貫して行える研究体制が極めて有効であった。対象疾患はいずれも治療薬が開発されていない疾患で、治療薬につながるリード化合物創製は社会的にも極めて大きな意義を持つ。さらに、本研究でその有効性が確認された阻害剤設計手法は、パンデミックが危惧されている新型コロナウイルスの治療薬開発にも応用可能な一般性を持っており、この点でも大きな意義を持つ。