Small-sized BACEl Inhibitors: In-silico Design and Synthesis

摘要

Amyloid p peptide (Aβ), the main component of senile plaques in the brain of Alzheimer's disease (AD) patients, is formed by proteolysis of amyloid precursor protein (APP). As β-secretase (BACEl: β-site APP cleaving enzyme 1) triggers Ap formation by cleavage at the Ap domain N-terminus, it is a molecular target for AD therapeutic intervention. We previously reported potent pentapeptidic and non-peptidic BACEl inhibitors containing a substrate transition-state mimic. Although these inhibitors exhibited potent inhibitory activities, their molecular-sizes appeared a little too big (MW>600) for developing practical drugs. In this study, we designed a series of small-sized BACEl inhibitors using a design approach based on the conformation of a virtual inhibitor bound to the BACEl active site. Moreover, we designed some small peptides with BACEl inhibitory activity.