Cyanobacterial Peptides as a Prototype for the Design of Potent beta-Secretase Inhibitors and the Development of Selective Chemical Probes for Other Aspartic Proteases
文献类型：期刊论文
| 作者 | Liu, YX ; Zhang, W ; Li, L ; He, JH（何建华） ; Xu, YC ; Li, YX ; Luesch, H |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2012 |
| 卷号 | 55期号:23 |
| ISSN号 | 0022-2623 |
| 英文摘要 | 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's disease. We probed the stereospecificity of target engagement and determined additional structure-activity 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 beta), membrane bound carboxyl terminal fragment (CTF), levels of beta-amyloid (A beta) peptides and selectivity for beta-secretase (BACE1) over gamma-secretase. Prioritized compounds showed reasonable stability in vitro and in vivo, and our most potent inhibitor showed efficacy in reducing A beta levels in the rodent brain. |
| 语种 | 英语 |
| WOS记录号 | WOS:000312227300038 |
| 公开日期 | 2013-09-11 |
| 源URL | [http://ir.sinap.ac.cn/handle/331007/13116]  |
| 专题 | 上海应用物理研究所_中科院上海应用物理研究所2011-2017年 |
| 推荐引用方式 GB/T 7714 | Liu, YX,Zhang, W,Li, L,et al. Cyanobacterial Peptides as a Prototype for the Design of Potent beta-Secretase Inhibitors and the Development of Selective Chemical Probes for Other Aspartic Proteases[J]. JOURNAL OF MEDICINAL CHEMISTRY,2012,55(23). |
| APA | Liu, YX.,Zhang, W.,Li, L.,He, JH.,Xu, YC.,...&Luesch, H.(2012).Cyanobacterial Peptides as a Prototype for the Design of Potent beta-Secretase Inhibitors and the Development of Selective Chemical Probes for Other Aspartic Proteases.JOURNAL OF MEDICINAL CHEMISTRY,55(23). |
| MLA | Liu, YX,et al."Cyanobacterial Peptides as a Prototype for the Design of Potent beta-Secretase Inhibitors and the Development of Selective Chemical Probes for Other Aspartic Proteases".JOURNAL OF MEDICINAL CHEMISTRY 55.23(2012). |
入库方式： OAI收割
来源：上海应用物理研究所
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