In vivo inhibition of Abeta production by memapsin 2 (beta-secretase) inhibitors.
We have previously reported structure-based design of memapsin 2 (beta-secretase) inhibitors with high potency. Here we show that two such inhibitors covalently linked to a "carrier peptide" penetrated the plasma membrane in cultured cells and inhibited the production of beta-amyloid (Abeta). Intraperitoneal injection of the conjugated inhibitors in transgenic Alzheimer's mice (Tg2576) resulted in a significant decrease of Abeta level in the plasma and brain. These observations verified that memapsin 2 is a therapeutic target for Abeta reduction and also establish that transgenic mice are suitable in vivo models for the study of memapsin 2 inhibition.
Chang
Wan-Pin
WP
Protein Studies Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA.
Koelsch
Gerald
G
Wong
Stephen
S
Downs
Deborah
D
Da
Huining
H
Weerasena
Vajira
V
Gordon
Brian
B
Devasamudram
Thippeswamy
T
Bilcer
Geoffrey
G
Ghosh
Arun K
AK
Tang
Jordan
J
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D010450:Endopeptidases; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000097:blood; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism
D016229:Amyloid beta-Peptides; D004337:Drug Carriers; D004791:Enzyme Inhibitors; C487905:Fs(OM00-3)DR9 peptide; C487904:Fs(OM99-2)tat peptide; D009842:Oligopeptides; D010446:Peptide Fragments; D010455:Peptides; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; D016650:Fluorescein-5-isothiocyanate