Therapeutic targeting of pathological proteins Flashcards
What are proteomics?
Accumulation of different misfolded disease-associated proteins, often within neurones, is a common feature of neurodegenerative disorders.
What are proteinpathies?
The conversion of soluble proteins into insoluble forms. Protein misfolding exposes normally buried hydrophobic AA residues which then form stable protein protein interactions.
What is evidence for removing protein aggregates improving disease?
Inducible expression of human MND-associated protein in mice. When expression is stopped with +Dox, pathological hTDP-43 can be cleared by endogenous pathways. Even after neurodegeneration TDP-43 led to neuron preservation.
What are the two pathways for intracellular protein degradation?
The ubiquitin proteasome system and the autophagy pathway (lysosome based)
What does the 26S proteasome consist of?
19S: binds to polyubiquitin chain on a substrate; uses ATP to unfold the substrate. 20S core contains protease subunits which digest the substrate.
What are degron sequences?
Specific E3 recognition motifs in substrate proteins. Direct binding of E3 to newly exposed degron sequences in misfolded UPS substrate proteins. Degron is exposed from UPS substrate recognition. Go to proteosome for degradation. (diagram is useful)
How does the autophagy pathway work?
Look up and write out steps.
What is an approach using 26 proteosome?
Developing small molecule activators of the 26 proteosome. But achieving selectivity is a challenge.
What are PROTACs (proteolysis targeting chimeras
Selectively induce targeted protein degradation through the UPS. Heterobifunctional molecules which contain a small molecule targeting the protein of interest (warhead 1) a small molecule (2) capable of recruiting an E3 ligase and a crosslinker (3) connecting the two moieties.
What is an advantage to PROTACs?
In contrast to traditional occupancy-based inhibitors that require sufficient binding affinities to druggable active sites PROTACs require only transient binding to target proteins to catalytically induce ubiquitination and degradation.
What was the first PROTAC made?
In 2008, degraded androgen receptor AR through its recruitment to the E3 ligase MDM2.
What is a limitation to PROTAC?
Although several thousand PROTACs have been developed, their major applications lie outside of neurodegenerative disorders as the UPS can’t clear protein aggregates. BUT utility in cancer treatments is very promising.
What do AUTACs do?
Promote autophagy-mediated clearance of disease-related debris. Contain a degradation tag and a warhead to provide target specificity.
What is an application of AUTACs?
S-Guanylation is cGMP-based PTM, induced by oxidative stress that can signal substrates selective for autophagy. Mito-AUTAC enhances mitochondria quality via removal of oxidatively damaged fragmented mitochondria.
