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In vivo inhibition of Aβ production by memapsin 2 (β‐secretase) inhibitors
Author(s) -
Chang WanPin,
Koelsch Gerald,
Wong Stephen,
Downs Deborah,
Da Huining,
Weerasena Vajira,
Gordon Brian,
Devasamudram Thippeswamy,
Bilcer Geoffrey,
Ghosh Arun K.,
Tang Jordan
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02452.x
Subject(s) - in vivo , potency , genetically modified mouse , chemistry , intraperitoneal injection , transgene , pharmacology , in vitro , amyloid (mycology) , peptide , biochemistry , biology , gene , inorganic chemistry , microbiology and biotechnology
We have previously reported structure‐based design of memapsin 2 (β‐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 β‐amyloid (Aβ). Intraperitoneal injection of the conjugated inhibitors in transgenic Alzheimer's mice (Tg2576) resulted in a significant decrease of Aβ level in the plasma and brain. These observations verified that memapsin 2 is a therapeutic target for Aβ reduction and also establish that transgenic mice are suitable in vivo models for the study of memapsin 2 inhibition.
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