# Small molecule induced proteolytic destruction of intrinsically disordered proteins

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2021 · $17,862

## Abstract

The significance: There are still no effective treatments for neurodegenerative diseases,
including Parkinson's and Alzheimer's disease and Alzheimer's related dementias.
The problem: The pathogenesis of these disorders are driven in large part by the toxic
signaling of amassed intrinsically disordered proteins (IDPs), such as α-synuclein or
(phosphorylated)-tau, which have a high tendency to oligomerize and aggregate upon
accumulation. During healthy homeostasis, IDPs are rapidly degraded by the 20S
proteasome and thus are short-lived and in near undetectable abundance. As we age,
proteasome activity is reduced and IDPs accumulate, leading to toxic signaling and
aggregation, which are the hallmarks of many neurodegenerative diseases. These unfolded
IDPs lack defined binding pockets, which made them evade traditional drug discovery design
efforts and are therefore often deemed “undruggable”. Of all human organs and tissues, the
brain expresses one of the highest levels of IDPs, and amassed levels of these highly
disordered IDPs have been directly linked to neurodegenerative disorders. No effective
treatments to prevent, stop or reverse these disorders are currently available.
The solution: Enhancing 20S proteasome activity should restore healthy protein homeostasis
and prevent the accumulation of disordered proteins.
Our approach: Instead of inhibiting IDPs with a drug, we will induce their proteolytic
destruction. Our hypothesis is that we can limit the toxic accumulation of IDPs by
enhancing/restoring 20S proteasomal degradation using small molecules. This approach is
different from all previous attempts to target IDP-instigated diseases. Our new data indicates
that 20S proteasome enhancements exhibits selectivity towards the toxic, highly disordered
oligomerization/aggregation-prone IDPs over other proteins that merely containing disordered
regions. Moreover, our preliminary data shows that the treatments do not induce cytotoxicity in
cells treated at high dose or following chronic exposure to the enhancers. This is an unexplored
field in science and human health and we will be one of the first to determine the possibilities
and limitations of this new approach in this work.

## Key facts

- **NIH application ID:** 10329154
- **Project number:** 3R01AG066223-02S1
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** JETZE J. TEPE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $17,862
- **Award type:** 3
- **Project period:** 2019-09-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10329154

## Citation

> US National Institutes of Health, RePORTER application 10329154, Small molecule induced proteolytic destruction of intrinsically disordered proteins (3R01AG066223-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10329154. Licensed CC0.

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