Developing innovative small-molecule lysosomal degraders for pathogenic protein aggregates in human disease
Active Project Grant Awarded Last action
- Award ID
- F31NS149735
- Recipient
-
University Of California Irvine UEI MJC5FCYQTPE6
- Awarding agency
-
National Institute of Neurological Disorders and Stroke
National Institutes of Health, Department of Health and Human Services
- Obligated
- $95,792
Award facts
- Assistance listing
- 93.853 Extramural Research Programs in the Neurosciences and Neurological Disorders
- Completion date 0% complete
- Originally
- Place of performance
- Irvine, CA 92697, USA
Award details come from USAspending.gov.
Description
- Abstract
- Protein aggregate formation is a central pathogenic mechanism underlying many diseases, yet remains largely undruggable, representing a major bottleneck for current therapeutic interventions. Targeted protein degradation (TPD) is an emergent, small molecule therapeutic approach that harnesses native cellular degradation pathways to eliminate disease-causing proteins. Small molecule proteolysis-targeting chimeras (PROTACS) recruit E3 ligases to a target protein that becomes ubiquitinated for proteasomal destruction. With over 25 PROTACS currently in clinical cancer trials, the promise of this field to revolutionize modern medicine is evident but limited by the capacity of proteasomes. PROTACS utilize the proteasome, which is limited for aggregates, and lacks tissue-specificity due to the ubiquitous expression of E3 ligases. Our goals aim to develop a novel approach to eliminate disease-causing aggregates. We developed a small-molecule technology, methyl arginine targeting chimera (MRTAC), which leverages proximity-induced degradation of proteins in lysosomes, which are uniquely equipped for the turnover of large protein assemblies and whole organelles. Recent work shows that arginine methylation modifications direct proteins to lysosomes during normal homeostatic maintenance in unmodified, natural conditions. Advantageously, MRTAC exploits arginine-methylation, an endogenous post-translational degradative modification for lysosomes by recruiting protein arginine methyltransferase enzymes (PRMTS) to catalyze this lysosomal-targeting modification on substrates. Dysregulation at the protein level underlies a wide range of human diseases, highlighting the potential of targeted protein degradation as a transformative therapeutic approach. Neurodegeneration is driven at the protein-level, suggesting that targeted degradation could transform therapeutics. We hypothesize MRTAC offers a novel, tissue-selective strategy to eliminate pathogenic protein aggregates. The proposal aims to establish a novel lysosomal degradation pathway using MRTAC to selectively eliminate pathogenic aggregates such as FUS, TAU, and αsyn (aim 1), and to leverage distinct PRMTS for achieving tissue-specificity and endogenous functionality of MRTAC (aim 2). At the completion of this work, we will have developed a novel approach for targeted protein degradation of protein aggregates, which will open an entirely novel therapeutic approach that overcomes the central limitations of current therapeutic strategies.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $47,896 | |
| Amendment | $47,896 | |
| Original award | $0 |
Quick answers
Who received award F31NS149735?
F31NS149735 was awarded to University Of California Irvine by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on December 1, 2026.
How much is award F31NS149735 worth?
$95,792 has been obligated on F31NS149735.
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