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

详细信息    查看全文

• 作者：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 O虆mura ; Toshiaki Sunazuka
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：June 25, 2015
• 年：2015
• 卷：58
• 期：12
• 页码：4984-4997
• 全文大小：744K
• ISSN：1520-4804

文摘

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 鈭?00-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.