LONG WAVELENGTH FLUORESCENT REPORTERS FOR PROTEIN KINASES AND DESIGN OF LIGHT-ACTIVATABLE BIOAGENTS Public Deposited

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  • March 19, 2019
Creator
  • Nguyen, Luong
    • Affiliation: Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
Abstract
  • The first part of this dissertation describes the development of wavelength-tunable fluorescent reporters for monitoring protein kinase activity. The probing wavelength is preprogrammed by using a variety fluorophores which are commercially available. Specifically, we develop fluorescent sensors sensing in the far-red and near-IR region and use them to monitor endogenous cAMP-dependent protein kinase activity in erythrocyte lysates and in erythrocytes. Stabilization of the peptide sensor in erythrocyte lysate is also reported. The study provides powerful tools to investigate the roles of protein kinase A activity in erythrocyte biochemistry, for example, in Plasmodium Falciparum infection and propagation. In the second part of the dissertation, we describe the design of light-activatable bioagents based on lipidation and membrane sequestration. A lipidated bioagent upon binding to cells/organelles' membrane is biologically inert. A photolabile group placed between the lipid and bioagent furnishes a means to release the bioagent from the membrane and activate it. The strategy provides a way to fine-tune the presence of a "active" bioagent using light. For example, a peptide sensor can be introduced into a biological system and remains "silent" until controllably activated with light; a protein can be activated or inhibited by the light-triggered release of the corresponding active activator or inhibitor that is hidden in the membrane. Additionally, the use of erythrocytes as carriers and protectors of photoactivatable peptide therapeutics is also discussed. The study is aim to develop a way to controllably deliver active therapeutics to a specific region of the body to increase their potency and reduce their toxicity.
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  • In Copyright
Advisor
  • Lawrence, David
  • Zhang, Qisheng
  • Parise, Leslie
  • Sims, Christopher
  • Jarstfer, Michael
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2014
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Place of publication
  • Chapel Hill, NC
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