Peptide aptamers against prion proteins as therapeutic and analytic tools Prion diseases are a unique group of infectious and fatal neurodegenerative disorders of man and animals characterized by spongiform degeneration in the central nervous system. A hallmark of these disorders is the accumulation of a misfolded and pathological isoform (PrPSc) of the host-encoded normal prion protein (PrPc), representing therefore a prototypic misfolding disease. A unique feature is that the manifestation can be sporadic, genetic, and acquired by infection. Examples are Creutzfeldt-Jakob disease (CJD/vCJD) in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and chronic wasting disease (CWD) in elk, moose and deer. Although the sporadic form of CJD is rare, it is found at a constant rate worldwide. Prion diseases can be transferred within and between species by infection processes and this can emerge to even epidemic scenarios. Of particular interest is CWD, being presently the most 'infectious'prion disease. It is spreading both geographically and in numbers and is basically not to control, as farmed and wild living animals are affected. Whether CWD has zoonotic potential as did BSE, resulting in the variant form of CJD, is presently not excluded. Another specialty of prions is that they use a mechanism of propagation and information encoding which is based solely on conformational changes of proteins and is without using nucleic acids for encoding information. Given these distinctive features, there are also a number of striking similarities with the more frequent neurodegenerative disorders, attributing prion diseases sometimes even model character. My group has significantly contributed to the identification of novel targets and strategies for interference in prion conversion, e.g. by triggering endogenous PrPSc/prion degradation capacity and inhibiting formation of PrPSc by altering PrPc trafficking or blocking PrPc-PrPSc interaction. To achieve the latter, we recently employed peptide aptamer technology. A combinatorial constrained peptide library embedded in the scaffold protein thioredoxin A (trxA) was made by us and screened by yeast-2-hybrid for PrP binding peptide aptamers. The identified peptide aptamers were characterized in prion-infected cells and found to significantly inhibit prion conversion dose- and time-dependently. For the first time, peptide aptamers were targeted to the secretory pathway in mammalian cells, and we could show that this manipulation did not alter the binding affinity for the target protein. Our studies were therefore of general impact not only for the prion field, but also for aptamer researchers, since we provided evidence that the range of target proteins for peptide aptamers can be extended to proteins expressed in the secretory pathway. With this application we want to extend our studies towards development and validation of therapeutically applicable anti-prion compounds and furthermore, to use peptide aptamers as analytic tool to address basic questions in prion biology and protein misfolding. Specifically, we want to use peptide aptamers for characterizing the PrPc-PrPSc interface and targeting prion folding intermediates. Our anti-prion compounds might be also of interest for Alzheimer's disease, as recent findings suggest that they might function as competitive inhibitors of A? toxicity. Overall, our studies will focus on new avenues for therapy of prion diseases and related disorders. In addition, we establish a new area of research at the University of Wyoming (prion biology and cellular and molecular neurodegeneration) and re-establish the existing prion infection oriented research, which has a historic background here. As our group is established in the field and well interconnected in international prion research, it is very likely that local and international students will be attracted to this research area and that this significantly contributes to the local research environment.

Public Health Relevance

Peptide aptamers against prion proteins as therapeutic and analytic tools The proposed project is relevant to public health because it extends studies towards development of anti-prion compounds. Using an innovative combinatorial technology it is intended to select and characterize tools which have the potential to interfere in prion infection and which can be used to address basic questions in prion biology and protein misfolding. Overall, these studies will focus on new avenues for therapy of prion diseases and related disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Academic Research Enhancement Awards (AREA) (R15)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Wong, May
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University of Wyoming
Veterinary Sciences
Schools of Earth Sciences/Natur
United States
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