Keqiang Ye
Emory University School of Medicine, USA
Title: Delta-secretase inhibitor for treating Alzheimer’s disease
Biography
Biography: Keqiang Ye
Abstract
Asparagine Endopeptidase (AEP) is implicated in various human disorders including cancers and neurodegenerative diseases. AEP is upregulated and activated in normally aged brain and human Alzheimer’s Disease (AD) brain, and plays a critical role in mediating the pathophysiology of AD. Here we report an orally bioactive and brain permeable AEP inhibitor that blocks the cleavage of tau and APP, and alleviates the cognitive deficits in mouse models of AD. We performed a high-throughput screen and discovered several compound families with potent inhibitory activity. After analyzing the druglikeness properties of the compounds, we identified a nontoxic and selective AEP inhibitor family, termed compound 11, that selectively blocks AEP but not other related cysteine proteases. Strikingly, co-crystal structure analysis revealed a dual active site-directed and allosteric inhibition mode of this compound class. Chronic treatment of tau P301S and 5XFAD transgenic mice with oral administration of the inhibitor reduces tau and APP cleavage, ameliorates synapse loss and augments Long-Term Potentiation (LTP), resulting in protection of memory. Therefore, these findings demonstrate that this AEP inhibitor may be an effective clinical therapeutic agent towards AD.