In vivo inhibition of Abeta production by memapsin 2 (beta-secretase) inhibitors

Wan-Pin Chang; Gerald Koelsch; Stephen Wong; Deborah Downs; Huining Da; Vajira Weerasena; Brian Gordon; Thippeswamy Devasamudram; Geoffrey Bilcer; Arun K Ghosh; Jordan Tang

doi:10.1111/j.1471-4159.2004.02452.x

In vivo inhibition of Abeta production by memapsin 2 (beta-secretase) inhibitors

J Neurochem. 2004 Jun;89(6):1409-16. doi: 10.1111/j.1471-4159.2004.02452.x.

Authors

Wan-Pin Chang¹, Gerald Koelsch, Stephen Wong, Deborah Downs, Huining Da, Vajira Weerasena, Brian Gordon, Thippeswamy Devasamudram, Geoffrey Bilcer, Arun K Ghosh, Jordan Tang

Affiliation

¹ Protein Studies Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA.

PMID: 15189343
DOI: 10.1111/j.1471-4159.2004.02452.x

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Alzheimer Disease / drug therapy*
Alzheimer Disease / metabolism
Amyloid Precursor Protein Secretases
Amyloid beta-Peptides / blood
Amyloid beta-Peptides / metabolism*
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

Substances

Amyloid beta-Peptides
Drug Carriers
Enzyme Inhibitors
Fs(OM00-3)DR9 peptide
Fs(OM99-2)tat peptide
Oligopeptides
Peptide Fragments
Peptides
amyloid beta-protein (1-40)
Amyloid Precursor Protein Secretases
Endopeptidases
Aspartic Acid Endopeptidases
BACE1 protein, human
Bace1 protein, mouse
Fluorescein-5-isothiocyanate