[SCAN] Brain permeant peptidomimetic β-secretase 1 inhibitor for the treatment of Alzheimer’s disease

Scan Seminar

Title: Brain permeant peptidomimetic β-secretase 1 inhibitor for the treatment of Alzheimer’s disease

Speaker: Helder Vila Real

From: Pharmacokinetics and Biopharmaceutical Analysis Lab, ITQB

Abstract:

Alzheimer’s disease (AD), a fast growing disease in industrial countries needs urgently a drug capable of blocking or delaying its progression. Beta-secretase (BACE-1) is one of two enzymes needed to produce amyloid beta (Abeta42) peptide and its inhibition is attractive as a therapeutic target, to avoid the formation of toxic oligomers of Abeta42 peptide that deposit in amyloid plaques of AD patients.
Treatment of AD through brain inhibition of BACE-1 is unfortunately a hard task. A first approach to accomplish this was based on the synthesis of peptidomimetic inhibitors that despite the good results obtained in vitro, failed in vivo. The large size and the hydrophilic nature of these inhibitors limit their permeation across the blood-brain barrier (BBB) by passive diffusion, so non-peptidic inhibitors have been developed. The smaller and hydrophobic non-peptidic inhibitors developed raised other issues including efflux by P-glycoprotein that also limits BBB permeation.
Considering this, we aim to overcome the BBB low permeability of BACE-1 inhibitors making use of a receptor-mediated transcytosis mechanism to permeate peptidomimetic BACE-1 inhibitors containing a targeting sequence for a BBB receptor. Herein we report promising results in order to accomplish this task.