Development of MTH1-binding nucleotide analogs based on 7,8-dihalogenated 7-deaza-dg derivatives

Hui Shi, Ren Ishikawa, Choon Han Heh, Shigeki Sasaki, Yosuke Taniguchi

研究成果: Contribution to journalArticle査読

抄録

MTH1 is an enzyme that hydrolyzes 8-oxo-dGTP, which is an oxidatively damaged nu-cleobase, into 8-oxo-dGMP in nucleotide pools to prevent its mis-incorporation into genomic DNA. Selective and potent MTH1-binding molecules have potential as biological tools and drug candidates. We recently developed 8-halogenated 7-deaza-dGTP as an 8-oxo-dGTP mimic and found that it was not hydrolyzed, but inhibited enzyme activity. To further increase MTH1 binding, we herein designed and synthesized 7,8-dihalogenated 7-deaza-dG derivatives. We successfully synthesized multiple derivatives, including substituted nucleosides and nucleotides, using 7-deaza-dG as a starting mate-rial. Evaluations of the inhibition of MTH1 activity revealed the strong inhibitory effects on enzyme activity of the 7,8-dihalogenated 7-deaza-dG derivatives, particularly 7,8-dibromo 7-daza-dGTP. Based on the results obtained on kinetic parameters and from computational docking simulating studies, these nucleotide analogs interacted with the active site of MTH1 and competitively inhibited the substrate 8-oxodGTP. Therefore, novel properties of repair enzymes in cells may be elucidated using new compounds.

本文言語英語
論文番号1274
ページ(範囲)1-13
ページ数13
ジャーナルInternational journal of molecular sciences
22
3
DOI
出版ステータス出版済み - 2 1 2021
外部発表はい

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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