Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive decline in cognitive function, depriving people of their memory and independent wellbeing.  The formation and accumulation of amyloid β (Aβ) peptides have been implicated in the pathology of AD.  The proteases β-secretase (BACE) and γ-secretase are responsible for generation of the toxic Aβ peptides through the sequential cleavage of the amyloid precursor protein (APP). Therefore, targeting these enzymes with small molecules has emerged as a promising approach for the treatment of AD.  Unfortunately, several structurally distinct BACE inhibitors have demonstrated ocular toxicity in animal models.  Using a clickable photoaffinity probe analog, we reveal that inhibition of cathepsin D (CatD) is the primary off-target of BACE inhibitors.  Additionally, we developed a parallel-medicinal chemistry (PMC) approach to access a suite of clickable BACE photoaffinity probes containing either a benzophenone, diazirine or aryl azide and compared the different probes in live cells.                <br/>

Design, synthesis and application of clickable β-secretase photoaffinity probes for (off-)target identification

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.