Discovery of a series of selective and cell permeable beta-secretase (BACE1) inhibitors by fragment linking with the assistance of STD-NMR |
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| Affiliation: | 1. Departament de Química Inorgànica, Universitat de Barcelona, Av. Diagonal 645, Barcelona 08028, Spain;2. Departament de Mineralogia, Cristal·lografia i Dipòsits Minerals, Universitat de Barcelona, Martí Franqués s/n, 08028 Barcelona, Spain;3. Unitat de Difracció de R-X, Centre Científic i Tecnològic de la Universitat de Barcelona (CCiTUB), Universitat de Barcelona, Solé i Sabarís 1-3, 08028 Barcelona, Spain |
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| Abstract: | Two β-secreatase (BACE1) inhibitors from natural products (cinnamic acid and flavone) were linked to furnish potent, cell permeable BACE1 inhibitors with noncompetitive mode of inhibition, with the assistance of saturated transfer difference (STD)-NMR technique. Some of these conjugates also exhibited selective BACE1 inhibition over other aspartyl proteases such as BACE-2 and renin, as well as poor cytotoxicity. Taken together, conjugates 4 represent a new series of BACE inhibitors warrants further investigation for their potential in Alzheimier’s disease therapy. |
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| Keywords: | Beta-secretase (BACE1) STD-NMR Luteolin P-hydroxy-cinnamic acid Noncompetitive inhibition AD" },{" #name" :" keyword" ," $" :{" id" :" k0035" }," $$" :[{" #name" :" text" ," _" :" Alzheimer’s disease BACE1" },{" #name" :" keyword" ," $" :{" id" :" k0045" }," $$" :[{" #name" :" text" ," _" :" beta site amyloid precursor protein cleaving enzyme 1 or beta-secretase FRET" },{" #name" :" keyword" ," $" :{" id" :" k0055" }," $$" :[{" #name" :" text" ," _" :" fluorescence resonance energy transfer STD" },{" #name" :" keyword" ," $" :{" id" :" k0065" }," $$" :[{" #name" :" text" ," _" :" Saturated Transfer Difference NP" },{" #name" :" keyword" ," $" :{" id" :" k0075" }," $$" :[{" #name" :" text" ," _" :" natural product |
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