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PROTAC constructs capable of eliminating excess amyloidogenic proteins, human pancreatic islet amyloid polypeptide (hIAPP) and human plasma amyloid A (hSAA)
The goal of the project is to develop efficient methods for the controlled removal of two selected proteins, human islet amyloid polypeptide (hIAPP / amylin) and human amyloid A protein (hSAA), using a PROTAC approach that enables targeted protein degradation. What IAPP and SAA have in common is that they are overproduced in pathological states: overexpression of SAA accompanies inflammation, while IAPP is produced in excess in states of insulin resistance. Both proteins tend to aggregate, and when present in excess, form progressively larger oligomers, which are then deposited as amyloids. Both IAPP and SAA are overexpressed in cells and can accumulate in the cytoplasm and are secreted into the plasma, where they can also form aggregates. The main proteolytic systems involved in the removal of redundant proteins are the 20S proteasome and its 19S-20S complex, called the 26S proteasome. This complex is a component of the ubiquitin-dependent proteolytic system (UPS), responsible for most intracellular proteolysis. To carry out degradation, the 26S proteasome needs a signal in the form of a polyubiquitin chain attached to the protein to be degraded. The degradron for the extracellularly circulating 20S proteasome can be a hydrophobic tag (HyT). Our goal is to create two types of chimeras, PROTAC and HyT-PD, which will be able to stimulate the degradation of hIAPP and hSAA in intracellular and extracellular environments, respectively. Both types of chimeras will contain an element that recognizes the target protein (warhead) and a hydrophobic motif (HyT) or ligand recruiting E3 ligase. We will test constructs with HyT for their ability to target proteins to the degradation pathway mediated by the 20S proteasome, while constructs with E3 ligand will be tested for targeting IAPP and SAA to the UPS.
Details
- Financial Program Name:
- OPUS
- Organization:
- Narodowe Centrum Nauki (NCN) (National Science Centre)
- Realisation period:
- unknown - unknown
- Research team leader:
- prof. dr hab. inż. Jacek Czub
- Supervisor unit:
- Faculty of Chemistry
- External institutions
participating in project: -
- Gdański Uniwersytet Medyczny (Poland)
- Uniwersytet Gdańsk (Poland)
- Request type:
- National Research Programmes
- Domestic:
- Domestic project
- Verified by:
- Gdańsk University of Technology
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