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

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.