Creation of Customized Bioactivity within a 14-Membered Macrolide Scaffold: Design, Synthesis, and Biological Evaluation Using a Family-18 Chitinase

Akihiro Sugawara, Nobuo Maita, Hiroaki Gouda, Tsuyoshi Yamamoto, Tomoyasu Hirose, Saori Kimura, Yoshifumi Saito, Hayato Nakano, Takako Kasai, Hirofumi Nakano, Kazuro Shiomi, Shuichi Hirono, Takeshi Watanabe, Hisaaki Taniguchi, Satoshi Omura, Toshiaki Sunazuka

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Argifin, a 17-membered pentapeptide, inhibits chitinase. As argifin has properties that render it unsuitable as a drug development candidate, we devised a mechanism to create the structural component of argifin that bestows the chitinase inhibition and introduce it into a 14-membered macrolide scaffold. Here we describe (1) the designed macrolide, which exhibits ∼200-fold more potent chitinase inhibition than argifin, (2) the binding modes of the macrolide with Serratia marcescens chitinase B, and (3) the computed analysis explaining the reason for derivatives displaying increased inhibition compared to argifin, the macrolide aglycone displaying inhibition in a nanomolar range. This promises a class of chitinase inhibitors with novel skeletons, providing innovative insight for drug design and the use of macrolides as adaptable, flexible templates for use in drug discovery research and development.

Original languageEnglish
Pages (from-to)4984-4997
Number of pages14
JournalJournal of Medicinal Chemistry
Volume58
Issue number12
DOIs
Publication statusPublished - 2015 Jun 25
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Creation of Customized Bioactivity within a 14-Membered Macrolide Scaffold: Design, Synthesis, and Biological Evaluation Using a Family-18 Chitinase'. Together they form a unique fingerprint.

  • Cite this

    Sugawara, A., Maita, N., Gouda, H., Yamamoto, T., Hirose, T., Kimura, S., Saito, Y., Nakano, H., Kasai, T., Nakano, H., Shiomi, K., Hirono, S., Watanabe, T., Taniguchi, H., Omura, S., & Sunazuka, T. (2015). Creation of Customized Bioactivity within a 14-Membered Macrolide Scaffold: Design, Synthesis, and Biological Evaluation Using a Family-18 Chitinase. Journal of Medicinal Chemistry, 58(12), 4984-4997. https://doi.org/10.1021/acs.jmedchem.5b00175