Late-stage structure diversification of peptides using biocatalysts

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15302
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47050:Environmental and natural pharmaceutical resources-related
• Research Institution: Hokkaido University
• Principal Investigator: Matsuda Kenichi 北海道大学, 薬学研究院, 講師 (50812301)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: 生体触媒 / ペプチド / 天然物 / 生合成 / 環状ペプチド

Outline of Final Research Achievements

Chemo-, regio-, stereoselective modifications of peptides is challenging. In this study, we aim to establish a method that enables rapid access to heavily modified peptides, by using biocatalysts. Specifically, we focus on a family of peptide cyclases and peptide prenyltransferases and aimed to elucidate their substrate scopes as well as their structural basis, which would lead to the establishment of efficient peptide modification techniques. During the research period, we extensively characterized several enzymes in vitro and successfully expanded substrate selectivity through rational protein engineering. Additionally, alkylated cyclic peptides were obtained from linear peptides through a cascade reaction using two biocatalysts in a one-pot manner.

Free Research Field

天然物化学

Academic Significance and Societal Importance of the Research Achievements

本研究では、等研究グループが独自に発見したペプチド環化酵素ファミリーおよびアルギニン選択的ビスプレニル化酵素に着目し、多数存在するホモログ酵素の比較解析を通じてその基質選択性発現メカニズムの構造的基盤の検証を進めた。これらの酵素ファミリーは非常に高い選択性でペプチドを修飾できるため、中分子医薬品モダリティとして注目される修飾環状ペプチドを簡便に合成し構造多様化するための有効な手段となりうる。実際、これらを組み合わせることで、鎖状ペプチドから中間体を精製することなく、アルキル化環状ペプチドがワンポット反応により得られた。