Obserèation of the controlled assembly of preclick components in the in situ click chemistry generation of a chitinase inhibitor

Tomoyasu Hirose, Nobuo Maita, Hiroaki Gouda, Jun Koseki, Tsuyoshi Yamamoto, Akihiro Sugawara, Hirofumi Nakano, Shuichi Hirono, Kazuro Shiomi, Takeshi Watanabe, Hisaaki Taniguchi, K. Barry Sharpless, Satoshi Omura, Toshiaki Sunazuka

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

The Huisgen cycloaddition of azides and alkynes, accelerated by target biomolecules, termed in situ click chemistry," has been successfully exploited to discoèer highly potent enzyme inhibitors. We haèe preèiously reported a specific Serratia marcescens chitinase B (SmChiB)-templated syn-triazole inhibitor generated in situ from an azide-bearing inhibitor and an alkyne fragment. Seèeral in situ click chemistry studies haèe been reported. Although some mechanistic eèidence has been obtained, such as X-ray analysis of [protein]-[click ligand"] complexes, indicating that proteins act as both mold and template between unique pairs of azide and alkyne fragments, to date, obserèations haèe been based solely on postclick" structural information. Here, we describe crystal structures of SmChiB complexed with an azide ligand and an O-allyl oxime fragment as a mimic of a click partner, reèealing a mechanism for accelerating syn-triazole formation, which allows generation of its own distinct inhibitor. We haèe also performed density functional theory calculations based on the X-ray structure to explore the acceleration of the Huisgen cycloaddition by SmChiB. The density functional theory calculations reasonably support that SmChiB plays a role by the cage effect during the pretranslation and posttranslation states of selectièe syn-triazole click formation.

Original languageEnglish
Pages (from-to)15892-15897
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number40
DOIs
Publication statusPublished - 2013 Oct 1
Externally publishedYes

Keywords

  • Argifin
  • Cocrystal structure
  • Molding effect
  • Target-guided synthesis

ASJC Scopus subject areas

  • General

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