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    Design, Synthesis, and Evaluation of Brain-Penetrant PACAP-Derived Glycopeptides for the Treatment of Neurodegeneration and Neuroinflammation

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    Author
    Apostol, Christopher Robert
    Issue Date
    2021
    Keywords
    Glycopeptides
    Neurodegeneration
    Neuroinflammation
    PACAP
    Advisor
    Polt, Robin
    
    Metadata
    Show full item record
    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction, presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Embargo
    Release after 09/30/2022
    Abstract
    Neurodegenerative disorders negatively impact the health of millions of people worldwide each year, and current therapeutic strategies only alleviate symptoms and exhibit little to no curative potential. Peptides comprise an important class of biological regulatory molecules that may be able to meet these concerns. Many endogenous peptides act as hormones, neuromodulators, secretagogues, and regulators of the inflammatory response. Furthermore, peptides are highly selective for their target receptors, leading to reduced side effect profiles, and they are regarded as non-toxic due to their metabolism yielding innocuous amino acids. However, progress in developing peptide drugs is hampered by their poor in vivo pharmacokinetic profiles, limited membrane permeability, and low oral bioavailability. Several chemical strategies including cyclization, N-methylation, lipidation, PEGylation, and incorporation of unnatural amino acids have been largely successful in improving the stability of peptides, but generally don’t elicit membrane penetration. One such chemical modification that can address the membrane permeability problem is glycosylation. Glycosylation has been demonstrated to improve water solubility and in vivo stability of peptides, and dramatically enhance penetration across biological membranes, most notably the blood-brain barrier (BBB). We have applied our glycosylation methodology to a variety of endogenous peptides, and this work summarizes the glycosylation of PACAP, a potential candidate for treating neurodegenerative disorders. Overall, we found that our PACAP glycopeptides exhibited superior stability in vitro and in vivo compared to their non-glycosylated counterparts while maintaining the intrinsic efficacy and potency of native PACAP. Most importantly, we found that our PACAP glycopeptides were able to penetrate the BBB in physiologically relevant concentrations and elicit neuroprotective and anti-inflammatory activities in animal models of Parkinson’s disease, stroke, and traumatic brain injury.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Chemistry
    Degree Grantor
    University of Arizona
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    Dissertations

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