Modification of bafilomycin structure to efficiently synthesize solid-state NMR probes that selectively bind to vacuolar-type ATPase

Hajime Shibata, Hiroshi Tsuchikawa, Tatsuru Hayashi, Nobuaki Matsumori, Michio Murata, Takeo Usui

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Bafilomycin (Baf) is one of the most potent inhibitors of vacuolar-type ATPase, which is strongly implicated in age-related diseases. However, the binding site of the antibiotic on the protein remains unclear because of the complexity of the structure of Baf bound to the target subunit in the transmembrane region. For conducting structural studies by applying solid-state NMR, which is one of the most promising methodologies available for structural analysis in membrane system, preparing bioactive fluorinated Baf analogues is essential. In this study two Baf analogues were carefully designed and efficiently synthesized through the convergent coupling of three segments. Biological evaluation revealed that the activity of 24-F-Baf was comparable to that of Baf, indicating its utility as a potential probe for solid-state NMR analysis. By contrast, desmethylated 24-F-Baf exhibited markedly diminished activity. The absence of two methyl groups caused a critical conformational change in the macrocyclic core structure necessary for binding to the target protein.

Original languageEnglish
Pages (from-to)915-924
Number of pages10
JournalChemistry - An Asian Journal
Volume10
Issue number4
DOIs
Publication statusPublished - Apr 2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Organic Chemistry

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