Structural Analysis of Simultaneous Activation and Inhibition of Gamma-Secretase Activity in Development of Drugs for Alzheimers disease

SignificanceThe majority of drugs that target membrane-embedded protease {gamma}-secretase show unusual biphasic activation-inhibition dose-response in cells, model animals, and humans. Semagacestat and avagacestat are two biphasic-drugs that can facilitate cognitive decline in patients with Alzheimers disease. Initial mechanistic studies showed that the biphasic-drugs, and pathogenic mutations, can produce the same type of changes in {gamma}-secretase activity. ResultsDAPT, semagacestat LY-411,575, and avagacestat are four drugs that show different binding constants, and biphasic activation-inhibition dose-response curves, for amyloid-{beta}-40 products in SHSY-5 cells. Multiscale molecular dynamics studies showed that all four drugs bind to the most mobile parts in presenilin structure, at different ends of the 29 [A] long active site tunnel. Combined results from structure-activity studies, showed that the biphasic dose-response curves are a result of modulation of {gamma}-secretase activity by concurrent binding of multiple drug molecules at each end of the active site tunnel. The drugs activate {gamma}-secretase by forcing the active site tunnel to open, when the rate-limiting step is the tunnel opening, and formation of the enzyme-substrate complex. The drugs inhibit {gamma}-secretase as uncompetitive inhibitors, by binding next to the substrate to dynamic enzyme structures that regulate processive catalysis. The drugs can modulate the production of different amyloid-{beta} catalytic intermediates, by penetrating into the active site tunnel to different depth with different binding affinity. The drugs and pathogenic mutations affect the same dynamic processes in {gamma}-secretase structure. ConclusionsBiphasic-drugs like disease-causing mutations can reduce the catalytic capacity of {gamma}-secretase and facilitate pathogenic changes in amyloid metabolism.