Fragment-based discovery of irreversible covalent inhibitors of cysteine proteases using chlorofluoroacetamide library

Chizuru Miura, Naoya Shindo, Kei Okamoto, Keiko Kuwata, Akio Ojida

研究成果: Contribution to journalArticle査読

1 被引用数 (Scopus)

抄録

Fragment-based approach combined with electrophilic reactive compounds is a powerful strategy to discover novel covalent ligands for protein target. However, the promiscuous reactivity often interferes with identification of the fragments possessing specific binding affinity to the targeted protein. In our study, we report the fragment-based covalent drug discovery using the chemically tuned weak reactivity of chlorofluoroacetamide (CFA). We constructed a small fragment library composed of 30 CFA-appended compounds and applied it to the covalent ligand screening for cysteine protease papain as a model protein target. Using the fluorescence enzymatic assay, we identified CFA-benzothiazole 30 as a papain inhibitor, which was found to irreversibly inactivate papain upon enzyme kinetic analysis. The formation of the covalent papain-30 adduct was confirmed using electrospray ionization mass spectrometry analysis. The activity-based protein profiling (ABPP) experiment using an alkynylated analog of 30 (i.e., 30-yne) revealed that 30-yne covalently labeled papain with high selectivity. These data demonstrate potential utility of the CFA-fragment library for de novo discovery of target selective covalent inhibitors.

本文言語英語
ページ(範囲)1074-1081
ページ数8
ジャーナルChemical and Pharmaceutical Bulletin
68
11
DOI
出版ステータス出版済み - 11 1 2020

All Science Journal Classification (ASJC) codes

  • 化学 (全般)
  • 創薬

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