Cysteine protease inhibitors reduce brain beta-amyloid and beta-secretase activity in vivo and are potential Alzheimer's disease therapeutics.
Beta-secretase inhibitors that lower brain beta-amyloid peptides (Abeta) are likely to be effective for treating Alzheimer's disease (AD). Irreversible epoxysuccinyl cysteine protease inhibitors are known to reduce brain Abeta and beta-secretase activity in the guinea pig model of human Abeta production. In this study, acetyl-L-leucyl-L-valyl-L-lysinal (Ac-LVK-CHO) is also shown to significantly reduce brain Abeta and beta-secretase activity and brain Abeta in the same model. Ac-LVK-CHO is structurally distinct from the epoxysuccinyl inhibitors and is a reversible cysteine protease inhibitor. The results suggest that cysteine protease inhibitors generally, and reversible cysteine protease inhibitors specifically, have potential for development as AD therapeutics.
Hook
Gregory
G
American Life Science Pharmaceuticals Inc., San Diego, CA 92121, USA. ghook@alspinc.com
Hook
Vivian Y H
VY
Kindy
Mark
M
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002401:Cathepsin B / Q000378:metabolism*; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; C525166:acetyl-L-leucyl-L-valyl-L-lysinal; D053829:Amyloid Precursor Protein Secretases; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L