The invention concerns peptide- and peptidomimetic-based activators of human 20S proteasome containing a C-terminal HbYX motif, capable of efficiently enhancing the degradation of misfolded and pathogenic proteins in cells. These activators are stable in human plasma and cell-permeable, allowing restoration of proteostasis and reduction of pathological protein aggregation associated with neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, ALS, and type II diabetes.
Designed activators are based on the Blm-pep peptide sequence, mimicking the natural Blm10 activator mechanism, and can be modified to improve bioavailability and proteolytic activity. Studies show that these compounds selectively stimulate 20S proteasome without activating the 26S proteasome, reducing potential side effects.
Application:
- Development of therapeutics for neurodegenerative diseases and type II diabetes,
- Tool for studying protein degradation mechanisms and proteostasis,
- Platform for designing novel 20S proteasome activators.
