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

doi:10.1021/acs.jmedchem.5b00175

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 journal › Article › peer-review

12 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 language	English
Pages (from-to)	4984-4997
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	58
Issue number	12
DOIs	https://doi.org/10.1021/acs.jmedchem.5b00175
Publication status	Published - 2015 Jun 25
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.5b00175

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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

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, vol. 58, no. 12, pp. 4984-4997. https://doi.org/10.1021/acs.jmedchem.5b00175

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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.",

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AU - Kimura, Saori

AU - Saito, Yoshifumi

AU - Nakano, Hayato

AU - Kasai, Takako

AU - Nakano, Hirofumi

AU - Shiomi, Kazuro

AU - Hirono, Shuichi

AU - Watanabe, Takeshi

AU - Taniguchi, Hisaaki

AU - Omura, Satoshi

AU - Sunazuka, Toshiaki

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

Abstract

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