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 (Abet...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	Journal of neurochemistry 2004-06, Vol.89 (6), p.1409-1416
Hauptverfasser:	Chang, Wan-Pin, Koelsch, Gerald, Wong, Stephen, Downs, Deborah, Da, Huining, Weerasena, Vajira, Gordon, Brian, Devasamudram, Thippeswamy, Bilcer, Geoffrey, Ghosh, Arun K, Tang, Jordan
Format:	Artikel
Sprache:	eng
Schlagworte:	Alzheimer Disease - drug therapy Alzheimer Disease - metabolism Amyloid beta-Peptides - blood Amyloid beta-Peptides - metabolism Amyloid Precursor Protein Secretases Animals Aspartic Acid Endopeptidases - antagonists & inhibitors Blood-Brain Barrier - drug effects Blood-Brain Barrier - physiology Brain - drug effects Brain - metabolism Cell Line Cell Membrane - metabolism Disease Models, Animal Dose-Response Relationship, Drug Drug Carriers - administration & dosage Drug Carriers - chemistry Drug Carriers - metabolism Drug Evaluation, Preclinical Endopeptidases Enzyme Inhibitors - chemistry Enzyme Inhibitors - metabolism Enzyme Inhibitors - pharmacology Fluorescein-5-isothiocyanate - analogs & derivatives Fluorescein-5-isothiocyanate - pharmacology Humans Injections, Intraperitoneal Mice Mice, Transgenic Oligopeptides - pharmacology Peptide Fragments - blood Peptides - administration & dosage Peptides - chemistry Peptides - metabolism
Online-Zugang:	Volltext
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Beschreibung
Zusammenfassung:	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.
ISSN:	0022-3042