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First-in-class peptide therapeutics for mitochondrial disorders: molecular mechanism of action and optimization of design

Award Number: R01AG065879
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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First-in-class peptide therapeutics for mitochondrial disorders: molecular mechanism of action and optimization of design - PROJECT SUMMARY Mitochondria are organelles that play a dominant role in energy metabolism and many other cellular processes. Mitochondrial dysfunction is associated with primary heritable diseases and aging-related declines in health, including chronic pathologies like cancer, diabetes and neurodegeneration. There are currently no cures for mitochondrial diseases. However, Szeto-Schiller (SS) peptides have emerged among the most promising therapeutics for promoting mitochondrial health. As shown by preclinical and clinical trials, and as exemplified by the lead compound SS-31 (Elamipretide), SS peptides show exceptionally broad therapeutic efficacy in treating mitochondrial dysfunction. Using a multidisciplinary approach, our research team has conducted the first in-depth analysis of the molecular mechanism of action (MoA) of SS peptides. Our work supports a unique mechanism in which SS peptides interact with cardiolipin-rich mitochondrial membranes and modulate general physical membrane properties, thereby underpinning their broad therapeutic potential. The objective of the proposed project is twofold. The first goal is to thoroughly understand the MoA of SS peptides. To this end, we will leverage our solid foundation of mechanistic insights to test, refine, and expand our working models using computational, reductionist, mitochondrial, and cellular systems. The second goal is to identify the physicochemical properties of SS peptides that are most critical to their mechanism. To this end, we will evaluate a series of rationally designed SS peptide constructs with variations in the tetrapeptide cationic/aromatic motif, using our established functional assays. With our highly interdisciplinary research team, we will approach these goals as three separate aims. First, we will address how SS peptides interact with lipid bilayers and modulate their physical properties using a combination of computational and biophysical approaches with biomimetic model membrane systems. This will render critical information on equilibrium peptide binding models, high resolution structural information on peptide conformational dynamics and interaction with lipid groups, and how peptides modulate membrane electrostatics, lipid structural dynamics, and bilayer polymorphic changes. Second, we will evaluate the effects of SS peptides on the structure and function of membranes from yeast and mammalian models. This will establish the sites of peptide interaction in the morphologically complex mitochondrion, how peptides affect the stability and assembly of membrane complexes, the distribution of lipids within mitochondria, and lipid turnover kinetics. Finally, using mitochondrial and cellular models, we will analyze the mechanisms by which SS peptides restore function under pathological conditions including oxidative stress, high calcium load, and amyloidogenic proteins involved in type II diabetes and Alzheimer’s disease. By this multi-tiered approach, our results will yield unprecedented insights into the mechanism of this class of therapeutics with particular relevance to aging-related diseases. Further, our peptide screen will inform the design of SS peptide variants with greater efficacy and/or bioavailability.


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: 2026 ( Subtotal = -$4,691 )
2026	2024	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Aging Research	000	5	8/17/2026	NON-COMPETING CONTINUATION	-$4,691
														Subtotal = -$4,691

Issue Date FY: 2024 ( Subtotal = $494,761 )
2024	2024	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Aging Research	000	5	5/9/2024	NON-COMPETING CONTINUATION	$494,761
														Subtotal = $494,761

Issue Date FY: 2023 ( Subtotal = $582,273 )
2023	2023	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Aging Research	000	3	1/27/2023	SUPPLEMENT FOR EXPANSION	$87,512
2023	2023	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Aging Research	001	4	5/8/2023	NON-COMPETING CONTINUATION	$494,761
														Subtotal = $582,273

Issue Date FY: 2022 ( Subtotal = $494,761 )
2022	2022	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Aging Research	000	3	5/18/2022	NON-COMPETING CONTINUATION	$494,761
														Subtotal = $494,761

Issue Date FY: 2021 ( Subtotal = $483,831 )
2021	2021	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Aging Research	000	2	5/19/2021	NON-COMPETING CONTINUATION	$483,831
														Subtotal = $483,831

Issue Date FY: 2020 ( Subtotal = $533,698 )
2020	2020	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Aging Research	000	1	9/9/2020	NEW	$533,698
														Subtotal = $533,698

Grand Total All Awards = $2,584,633

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First-in-class peptide therapeutics for mitochondrial disorders: molecular mechanism of action and optimization of design

Award Number: R01AG065879

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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