Expanding Target Enabling Packages for AMP-AD Target Validation to identify small molecule inhibitors that block protein-protein interactions in cells

Sage Bionetworks, Seattle WA

Investigators

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Abstract

Abstract We recently developed compounds aimed at disrupting the interactions between CD44 and FERM proteins; an interaction believed to be pathological in Alzheimer?s disease (AD). We developed small molecules: 1) using in silico docking at the site where CD44 would bind to FERM proteins, 2) Validated the binding using microscale thermophoresis (MST) and surface plasmon resonance (SPR) and 3) validated disruption of CD44 peptide binding to FERM proteins using MST. We are now developing assays to validate binding in the cell using cellular thermal shift assay (CETSA) and fluorescently tagged CD44 to define the disruption between CD44 and FERM proteins. We are also starting to implement assays to define compounds that have a potential to be neuroprotective. Since these proteins were found to be upregulated in microglia, we are developing flow assays to measure the effect of compounds for microglia-specific functions such as oxidative stress and phagocytosis. These functions will be helpful in further developing the compounds for future development of therapeutics for AD.