Journal of medicinal chemistry · 2015
Creation of Customized Bioactivity within a 14-Membered Macrolide Scaffold: Design, Synthesis, and Biological Evaluation Using a Family-18 Chitinase.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Sugawara Akihiro, Maita Nobuo, Gouda Hiroaki, Yamamoto Tsuyoshi, Hirose Tomoyasu, Kimura Saori, Saito Yoshifumi, Nakano Hayato, Kasai Takako, Nakano Hirofumi, Shiomi Kazuro, Hirono Shuichi, Watanabe Takeshi, Taniguchi Hisaaki, Omura Satoshi, Sunazuka Toshiaki
Аннотация
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.