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β-Secretase inhibitors that lower brain β-amyloid peptides (Aβ) are likely to be effective for treating Alzheimer's disease (AD). Irreversible epoxysuccinyl cysteine protease inhibitors are known to reduce brain Aβ and β-secretase activity in the guinea pig model of human Aβ production. In this study, acetyl- l -leucyl- l -valyl- l -lysinal (Ac-LVK-CHO) is also shown to significantly reduce brain Aβ and β-secretase activity and brain Aβ 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.

Cysteine protease inhibitors reduce brain β-amyloid and β-secretase activity in vivo and are potential Alzheimer's disease therapeutics