Fluorescence lifetime platform to discover small-molecule inhibitors of tau and alpha-synuclein oligomerization.

Project SummaryIn this Phase I STTR projectPhotonic Pharma LLCPPin collaboration with the University of MinnesotaUMNwill establish a technology platform for high throughput screeningHTSto discover small molecule inhibitors of pathological self association of tau andsynucleinsynOligomers of these proteins are implicated in the pathologyseverityand progression of Alzheimer s diseaseADand Alzheimer s disease related dementiaADRDThis is novel and distinct from previous strategies that have unsuccessfully targeted fibrillar tausynThuscompounds that selectively target tau tau andsynsyn interactions within toxic oligomers are urgently neededPP s proprietary combination of fluorescent biosensor engineering and fluorescence lifetimeFLTdetection provides the capability to detectwith precisiontimes greater than conventional HTS technologysmall changes in protein structure and interactions in cells and cell free systemsThis precision is essential for reliable detection of structural changes within these toxic oligomersAimwill optimize our tau andsyn live cell and cell free biosensorsscaling up production and seeking the sensitivity and reproducibility needed to perform primary HTS on ak compound CNS focused chemical collectionMultiple orthogonal approaches are taken to ensure targeting of oligomers as opposed to fibrilsOur biosensors have shown effectiveness and robustness in pilot HTS with small libraries of known biologically active compoundsZandgtfor both sensorsindicating high assay qualityFrom these pilot screenswe have identified Hits with saturable FRET profilesfunctional efficacyand direct target engagementThese Hits will serve as tool compounds for FRET assay optimization as we scale up for thek compound HTSFollowing those screensHitsmolecules that attenuate FRET bySDwill undergo concentrationresponse rescreening to determine their apparent potencyECfor the modulation of tau tau orsynsyn interactionsseeking compounds with sub micromolar affinity and saturable responseAimwill apply secondary assays to determine the functional relevance and mechanism of actionMOAof Hits identified in AimThe most potent Hits will be prioritized for functional analysis in an overexpression model of tausyn induced cytotoxicityThese functional Hits will then be parsed using cell free biosensors to identify potential directon targetversus indirect MOAHits with direct MOAs will be further characterized with orthogonal biochemicalbiophysical and functional assaysThis Phase I project will validate a large scale HTS platform and initiate the Hit to Lead process for Hits that interact with tau orsynA subsequent Phase II project will evaluate in detail MOA and structure activity relationships and initiate pre clinical animal studies for the most potent compoundsWe have formed collaborations with experts in AD and ADRD and with executives in the pharmaceutical industryto ensure that the lead compounds discovered in this project will be further developed for therapeutic discovery Project Narrative Photonic Pharma LLCin collaboration with the University of Minnesotaproposes to apply novel drugdiscovery technology to develop effective therapies for Alzheimer s diseaseADand Alzheimer s disease related dementiaADRD