Abstract
Heparan sulfate (HS) regulates processing of the amyloid precursor protein by the Alzheimer's beta-secretase (BACE-1). An HS analogue, porcine intestinal mucosal heparin, was systematically modified at the principal positions of O-sulfation and N-sulfation/acetylation and tested for BACE-1 inhibitory and anti factor Xa activities. The derivative with the highest anti-BACE-1 to anti-Xa activity ratio contained N-acetyl and 2-O- and 6-O-sulfates and also exhibited attenuated activities against cathepsin-D and renin, two other structurally related aspartyl proteases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / enzymology
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Amyloid Precursor Protein Secretases
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Animals
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Anticoagulants / chemical synthesis
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Anticoagulants / chemistry
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Aspartic Acid Endopeptidases / chemistry
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Cathepsin D / antagonists & inhibitors
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Cathepsin D / chemistry
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Cattle
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Endopeptidases / chemistry*
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Factor Xa / chemistry
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Factor Xa Inhibitors*
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Heparin / analogs & derivatives*
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Heparin / chemical synthesis*
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Heparin / chemistry
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Heparitin Sulfate / analogs & derivatives*
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Heparitin Sulfate / chemical synthesis*
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Heparitin Sulfate / chemistry
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / chemistry
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Renin / antagonists & inhibitors
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Renin / chemistry
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Structure-Activity Relationship
Substances
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Anticoagulants
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Factor Xa Inhibitors
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Protease Inhibitors
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Heparin
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Heparitin Sulfate
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Amyloid Precursor Protein Secretases
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Endopeptidases
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Factor Xa
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Aspartic Acid Endopeptidases
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Renin
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Cathepsin D