Cyanobacterial Peptides as a Prototype for the Design of Potent 尾-Secretase Inhibitors and the Development of Selective Chemical Probes for Other Aspartic Proteases

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• 作者：Yanxia Liu ; Wei Zhang ; Li Li ; Lilibeth A. Salvador ; Tiantian Chen ; Wuyan Chen ; Kevin M. Felsenstein ; Thomas B. Ladd ; Ashleigh R. Price ; Todd E. Golde ; Jianhua He ; Yechun Xu ; Yingxia Li ; Hendrik Luesch
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：December 13, 2012
• 年：2012
• 卷：55
• 期：23
• 页码：10749-10765
• 全文大小：851K
• 年卷期：v.55,no.23(December 13, 2012)
• ISSN：1520-4804

文摘

Inspired by marine cyanobacterial natural products, we synthesized modified peptides with a central statine-core unit, characteristic for aspartic protease inhibition. A series of tasiamide B analogues inhibited BACE1, a therapeutic target in Alzheimer鈥檚 disease. We probed the stereospecificity of target engagement and determined additional structure鈥揳ctivity relationships with respect to BACE1 and related aspartic proteases, cathepsins D and E. We cocrystallized selected inhibitors with BACE1 to reveal the structural basis for the activity. Hybrid molecules that combine features of tasiamide B and an isophthalic acid moiety-containing sulfonamide showed nanomolar cellular activity. Compounds were screened in a series of rigorous complementary cell-based assays. We measured secreted APP ectodomain (sAPP尾), membrane bound carboxyl terminal fragment (CTF), levels of 尾-amyloid (A尾) peptides and selectivity for 尾-secretase (BACE1) over 纬-secretase. Prioritized compounds showed reasonable stability in vitro and in vivo, and our most potent inhibitor showed efficacy in reducing A尾 levels in the rodent brain.