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

thesis
posted on 2024-05-17, 14:44 authored by Christine S MuliChristine S Muli

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 (1) the preferential structural properties of peptide-conjugated unnatural substrates for different proteasome isoforms’ substrate channels, (2) the effectiveness of an immunoproteasome-targeting peptide-conjugated prodrug strategy, and (3) 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.

Funding

Investigating the Interaction of a Selective Peptoid Probe and Rpn-13, A Non-Essential Ubiquitin Receptor of the Proteasome

National Cancer Institute

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Development of Activity-Based Chemical Reporters to Differentiate Proteasome Isoforms in Cells

National Institute of General Medical Sciences

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Monitoring and Manipulating the Activity of the Immunoproteasome with Small Molecules

National Institute of Allergy and Infectious Diseases

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History

Degree Type

  • Doctor of Philosophy

Department

  • Medicinal Chemistry and Molecular Pharmacology

Campus location

  • West Lafayette

Advisor/Supervisor/Committee Chair

Darci J. Trader

Additional Committee Member 2

Rong Huang

Additional Committee Member 3

Emily Dykhuizen

Additional Committee Member 4

Jeremy Lohman