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2019 Fiscal Year Final Research Report

Synthesis of hloroalkene-type peptide bond isosteres and its medicinal application

Research Project

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Project/Area Number 16H06217
Research Category

Grant-in-Aid for Young Scientists (A)

Allocation TypeSingle-year Grants
Research Field Drug development chemistry
Research InstitutionShizuoka University

Principal Investigator

Narumi Tetsuo  静岡大学, 工学部, 准教授 (50547867)

Project Period (FY) 2016-04-01 – 2020-03-31
Keywordsペプチド結合 / バイオイソスター / 水素結合 / アミロイド
Outline of Final Research Achievements

Through the synthetic studies of (Z)-chloroalkene-type ADIs (alkene dipeptide isosteres) for developing non-hydrolyzable peptidomimetics of human neuromedin U receptor 2 peptidic agonists, we have shown that the combination of SET reduction and asymmetric alkylation offers promising access to the precursors of the Arg-Asn-type ADIs. Also, the stereoselective synthesis of (Z)-chloroalkene-type ADIs containing alpha,alpha-disubstituted amino acids was established. Functional analyses revealed the unique characters of (Z)-chloroalkene-type ADIs, including the mimic effect of intraresidue H-bonding interactions. The amide-to-alkene isosteric switching strategy with the combination use of (Z)-chloroalkene-type and (E)-methylalkene-type peptidomimetics revealed the details of the contributions of H-bonding interactions in amyloid fibril formation.

Free Research Field

創薬化学

Academic Significance and Societal Importance of the Research Achievements

ペプチド結合の等価置換は、ペプチドの易水解性の問題に応える分子技術であり、これまでアルケン型やフルオロアルケン型が広く用いられてきた。本研究の学術的意義は、これまで未開拓であったクロロアルケン型ペプチド結合等価体が、酸化耐性やp型水素結合のミミック効果など、他のアルケン型等価体には見られない特異な分子特性を有していることを示した点にある。クロロアルケン型ペプチド結合等価体に大きな創薬的価値を見出し、ペプチド創薬に有用なバイオイソスターを提供する点において、本研究の社会的意義は高いと評価できる。

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Published: 2021-02-19  

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