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Cyanobacterial Peptides as a Prototype for the Design of Potent beta-Secretase Inhibitors and the Development of Selective Chemical Probes for Other Aspartic Proteases
Liu, YX; Zhang, W; Li, L; He, JH(何建华); Xu, YC; Li, YX; Luesch, H
2012
Source PublicationJOURNAL OF MEDICINAL CHEMISTRY
ISSN0022-2623
Volume55Issue:23
AbstractInspired 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.
Language英语
Funding Project应物所项目组
WOS IDWOS:000312227300038
Citation statistics
Cited Times:28[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.sinap.ac.cn/handle/331007/13116
Collection中科院上海应用物理研究所2011-2019年
Recommended Citation
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).
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