title: Cyanobacterial peptides as a prototype for the design of potent β-secretase inhibitors and the development of selective chemical probes for other aspartic proteases.
abstract: 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 (sAPPβ), membrane bound carboxyl terminal fragment (CTF), levels of β-amyloid (Aβ) peptides and selectivity for β-secretase (BACE1) over γ-secretase. Prioritized compounds showed reasonable stability in vitro and in vivo, and our most potent inhibitor showed efficacy in reducing Aβ levels in the rodent brain.
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, United States.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Lilibeth A
authors.initials: LA
authors.lastname: Salvador
authors.forename: Tiantian
authors.initials: T
authors.lastname: Chen
authors.forename: Wuyan
authors.initials: W
authors.lastname: Chen
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Felsenstein
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Ladd
authors.forename: Ashleigh R
authors.initials: AR
authors.lastname: Price
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.forename: Jianhua
authors.initials: J
authors.lastname: He
authors.forename: Yechun
authors.initials: Y
authors.lastname: Xu
authors.forename: Yingxia
authors.initials: Y
authors.lastname: Li
authors.forename: Hendrik
authors.initials: H
authors.lastname: Luesch
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D057055:Aspartic Acid Proteases / Q000737:chemistry*; D000458:Cyanobacteria / Q000737:chemistry*; D015195:Drug Design; D008958:Models, Molecular; D015335:Molecular Probes; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D015335:Molecular Probes; D010455:Peptides; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D057055:Aspartic Acid Proteases