• Refine Query
  • Source
  • Publication year
  • to
  • Language
  • No language data
  • Tagged with
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

PEPTIDOMIMETIC APPROACHES FOR TARETING PROTEASOME SUBUNITS BETA-5I AND RPN-13 FOR ALTERNATIVE HEMATOLOGICAL CANCER THERAPIES

Christine S Muli (14227157) 17 May 2024 (has links)
<p>The proteasome is a multi-catalytic, multiprotein enzymatic machinery that is responsible for most of the protein degradation in the cell. Cellular protein homeostasis through the proteasome is regulated through the ubiquitin-independent or ubiquitin-dependent degradation pathway, which both utilize different isoforms of the enzymatic machinery. Over the past twenty years, the proteasome has been a well-validated therapeutic target by inhibition of its catalytic particle function, and more recently, through targeted protein degradation with the use of proteolysis targeting chimeras (PROTACs). Inhibition of the proteasome’s catalytic function has been previously shown to be therapeutically advantageous due to the need for high proteasomal activity for the survival of hematological cancer cells, which produce an overabundance of misfolded and unwanted proteins. Despite this success, off-target toxicities and drug-resistant mechanisms remain as dose-limiting factors for proteasome catalytic inhibition. Herein, we describe a variety of peptidomimetic (or “peptide-like”) approaches that target the proteasome beyond standard catalytic inhibition to serve as alternative therapies for hematological cancer. We investigate <em>(1)</em> the preferential structural properties of peptide-conjugated unnatural substrates for different proteasome isoforms’ substrate channels, <em>(2)</em> the effectiveness of an immunoproteasome-targeting peptide-conjugated prodrug strategy, and <em>(3)</em> the unknown binding site of a peptoid probe on the proteasome’s non-catalytic ubiquitin receptor, Rpn-13. This work not only showcases novel strategies to target the proteasome system but also describes methods that could be applied to other challenging enzymes or non-catalytic protein targets.</p>

Page generated in 0.0301 seconds