PT  - JOURNAL ARTICLE
AU  - Željko M. Svedružić
AU  - Katarina Vrbnjak
AU  - Manuel Martinović
AU  - Vedran Miletić
TI  - Structural Analysis of Simultaneous Activation and Inhibition of γ-Secretase Activity in Development of Drugs for Alzheimer’s disease
AID  - 10.1101/2020.09.22.307959
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.09.22.307959
4099  - http://biorxiv.org/content/early/2020/09/22/2020.09.22.307959.short
4100  - http://biorxiv.org/content/early/2020/09/22/2020.09.22.307959.full
AB  - Significance The majority of drugs that target membrane-embedded protease γ-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 Alzheimer’s 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-β-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 Å long active site tunnel. Combined results from structure-activity studies, showed that the biphasic dose-response curves are a result of modulation of γ-secretase activity by concurrent binding of multiple drug molecules at each end of the active site tunnel. The drugs activate γ-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 γ-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-β 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 γ-secretase structure.Conclusions Biphasic-drugs like disease-causing mutations can reduce the catalytic capacity of γ-secretase and facilitate pathogenic changes in amyloid metabolism.Competing Interest StatementThe authors have declared no competing interest.