Heparin derivatives as inhibitors of BACE-1, the Alzheimer's beta-secretase, with reduced activity against factor Xa and other proteases.
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.
Patey
Susannah J
SJ
School of Biological Sciences, University of Liverpool, Liverpool, L69 7ZB, United Kingdom.
Edwards
Elizabeth A
EA
Yates
Edwin A
EA
Turnbull
Jeremy E
JE
D000544:Alzheimer Disease / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002402:Cathepsin D / Q000037:antagonists & inhibitors / Q000737:chemistry; D002417:Cattle; D010450:Endopeptidases / Q000737:chemistry*; D015951:Factor Xa / Q000737:chemistry; D065427:Factor Xa Inhibitors; D006493:Heparin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D006497:Heparan Sulfate / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D012083:Renin / Q000737:chemistry; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D053829:Amyloid Precursor Protein Secretases; D000925:Anticoagulants; D016282:Aspartic Acid Endopeptidases; D002402:Cathepsin D; D010450:Endopeptidases; D015951:Factor Xa; D065427:Factor Xa Inhibitors; D006493:Heparin; D006497:Heparan Sulfate; D011480:Protease Inhibitors; D012083:Renin; D000092502:Renin Inhibitors