Structural Analysis of Simultaneous Activation and Inhibition of Gamma-Secretase Activity in Development of Drugs for Alzheimer's Disease published on bioRxiv
Our research preprint titled Structural Analysis of Simultaneous Activation and Inhibition of Gamma-Secretase Activity in Development of Drugs for Alzheimer's Disease, authored by Željko Svedružić, Katarina Vrbnjak, Manuel Martinović, and Vedran Miletić, has been uploaded to bioRxiv.
Abstract
Significance: The 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 γ-secretase activity.
Results: DAPT, 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.
Conclusions: Biphasic-drugs like disease-causing mutations can reduce the catalytic capacity of gamma-secretase and facilitate pathogenic changes in amyloid metabolism.