In vivo inhibition of Aβ production by memapsin 2 (β-secretase) inhibitors

Development of clinically useful memapsin 2 (BACE1) inhibitors is generally thought to be very challenging because they must be small enough (generally < 500 Da) to penetrate the blood–brain barrier (BBB) yet manifest high potency and other desirable pharmaceutical properties. Previously, the authors reported structure-based design of memapsin 2 inhibitors, Fs[OM99-2] and Fs[OM00-3], with high potency but poor BBB penetration. To increase BBB and cellular permeability carrier proteins (CPs) tat and DR9 were covalently linked to these two inhibitors; the conjugated inhibitors were delivered by i.p. injection to Tg2576 mic. The data showed that treatment of Tg mice with CP-linked inhibitors resulted in significant decrease of Aβ levels in the plasma and brain.