Therapeutic Potential Of Peptides Derived From Intrinsically Disordered Protein Regions

The conformational duality of the prion protein translates into strikingly distinct fates this protein can impart on the living systems. In one case, the outcome is the irrevocable neurodegeneration and fatal disease. In stark contrast, the cellular form of the prion protein (PrPc) partakes in life-sustaining cellular functions that include neuroprotection, signal transduction, and angiogenesis. Importantly, PrPc has been shown to be involved in a natural response to vascular injury, with the cell damage and death due to stroke being significantly increased in its absence. In vascular injury, including stroke, one of the key cell death-triggering events is the release of toxic levels of free hemin. A potential solution to this damage is a peptide therapeutic agent that would neutralize hemin, thus reducing deleterious effects of bleeding. Both the hemorrhagic and ischemic stroke (with “microbleeds” inflicting secondary damage) would benefit from this approach. Using biophysical methods, we have identified a peptide derived from the intrinsically disordered PrPc N-terminus and tested a hypothesis that this hemin-sequestering fragment could bind and neutralize hemin leading to reduction in brain damage due to bleeding. We employed fluorescence, surface plasmon resonance, and a well-established mouse model of intracerebral hemorrhagic stroke (ICH) to carry out these studies. Neurological/behavioral deficiencies and brain tissue damage caused by stroke were tested in the presence and absence of the peptide treatment. Our results indicate that the peptide derived from the intrinsically disordered prion domain binds hemin and reduces deleterious effects of stroke in-vivo, making it a strong candidate for further development as a novel therapeutic intervention in vascular injury events.