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New Drug Discovery Paradigms for Synucleinopathies

Award Number: R21AG055047
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2017
PERIOD OF PERFORMANCE END DATE: 04/30/2020

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New Drug Discovery Paradigms for Synucleinopathies - Summary: New Drug Discovery Paradigms for Synucleinopathies Dysfunction in cellular proteostasis leads to abnormal accumulation of misfolded proteins implicated in the pathology of several neurodegenerative diseases. Alpha-synuclein (aS) is the primary component of intracellular inclusions known as Lewy bodies—the cytopathological hallmark of Lewy body dementias, Parkinson’s disease and a frequent pathology in Alzheimer’s disease (AD). Both aS and tau pathology may overlap in AD because of the potential for inter-nucleation and aggregation of these two proteins. Thus, synucleinopathy is a high-priority target that bridges several CNS protein-misfolding disorders. Alpha-synuclein is a 140-amino-acid intracellular protein. It is an intrinsically disordered monomer but can adopt multiple - helical conformations on binding to lipid vesicles. This transition from disordered to -helical conformations is thought to lead to the formation of misfolded -sheet-rich structures that can form soluble oligomers and aggregates. Our hypothesis is that aS dimerization induced by membrane phospholipids is an early, rate- limiting step in protein-misfolding pathways that ultimately leads to synucleinopathies; and that a drug inhibiting this step will have therapeutic value. We have developed an ex vivo split-luciferase protein complementation assay to detect the initial dimerization of aS as it oligomerizes and aggregates. Our proposal is to use this assay in two innovative, high throughput screening (HTS) paradigms to identify novel aS aggregation inhibitors. One approach will take the standard long road to identify novel small molecules. We will screen 100,000 compounds in assay buffer conditioned with phospholipids that enhance aS dimerization. A panel of secondary assays will be used to characterize confirmed HTS hits for specificity, potency, mode of action and cellular activity. The expected Aim 1 milestone is identification of a novel lead suitable for nomination as a preclinical drug development candidate. Because of the mismatch between the small sizes of drug-like molecules compared to the expansive surface area involved in protein-protein interactions (PPI), HTS for protein-misfolding inhibitors is challenging. To potentially accelerate getting new therapies to the clinic, we propose a more unconventional approach in which we will attempt to identify a combination of two FDA approved drugs acting supra-additively by allosteric synergy to prevent the self-association and aggregation of aS. We will use a multiplexed-HTS method we developed for screening mixtures of FDA-approved drugs to discover combinations that stabilize monomeric aS structure, preventing self-association. The expected Aim 2 milestone is identification of a combination of two previously approved drugs that can potentially advance to proof-of-concept clinical testing for treating synucleinopathies faster than an individual new chemical entity. If successful, the new approaches we develop to discover novel PPI modulators could have broader utility for advancing understanding of other neurodegenerative diseases caused by protein misfolding and aggregation.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Aging Research	000	2	5/18/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $201,111 )
2018	2018	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Aging Research	001	2	6/22/2018	NON-COMPETING CONTINUATION	$0
2018	2018	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Aging Research	000	2	4/27/2018	NON-COMPETING CONTINUATION	$201,111
														Subtotal = $201,111

Issue Date FY: 2017 ( Subtotal = $258,676 )
2017	2017	LANKENAU INSTITUTE FOR MEDICAL RESEARCH	100 E LANCASTER AVE	WYNNEWOOD	PA	19096	MONTGOMERY	USA	Aging Research	000	1	7/28/2017	NEW	$258,676
														Subtotal = $258,676

Grand Total All Awards = $459,787

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New Drug Discovery Paradigms for Synucleinopathies

Award Number: R21AG055047

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2017

PERIOD OF PERFORMANCE END DATE: 04/30/2020

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