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Chemical Tools to Inhibit and to Modify Proteins

Cacace, Mary Frances (2024) Chemical Tools to Inhibit and to Modify Proteins. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The field of chemical biology has delivered diverse chemical tools that have been developed to answer fundamental biological questions. These chemical tools include small molecules, peptides, and oligonucleotides, which have been chemically modified for perturbing, profiling, modifying, and visualizing biomacromolecules. Herein, I detail my contributions to the fields of sulfotransferase biology and covalent protein modification through the development of small molecule- and oligonucleotide-based chemical tools to perturb, profile, and modify proteins. First, I describe the design and synthesis of novel isoform-specific allosteric inhibitors of two sulfotransferases, SULT1A3 and SULT2B1b, which regulate neurotransmitter and cholesterol metabolism, respectively. The allosteric inhibitors detailed within represent an entirely innovative approach to the inhibition of an ‘undruggable’ enzyme class that has immense implications in human diseases such as major depression, Alzheimer’s, and cancer.
I then transition from small-molecule-based to nucleic acid-based tools, and present covalent aptamers as versatile tools for endogenous protein modification and inhibition. The aptamers are functionalized with cleavable electrophiles that transfer functional labels to nucleophilic residues on protein targets. My efforts have driven the extension of this protein labeling approach from a test tube to the cell surface, modifying cancer biomarkers for various biological applications.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Cacace, Mary Francesmac519@pitt.edumac519
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee MemberChilders, W. Sethwschild@pitt.edu
Committee MemberFloreancig, Paulflorean@pitt.edu
Committee MemberBeumer, Janbeumerjh@upmc.edu
Committee ChairDeiters, Alexanderdeiters@pitt.edu
Date: 8 May 2024
Date Type: Publication
Defense Date: 30 November 2023
Approval Date: 8 May 2024
Submission Date: 12 March 2024
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 296
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: sulfotransferases, inhibitors, covalent protein modification, activity-based probes, aptamers
Date Deposited: 08 May 2025 12:20
Last Modified: 08 May 2025 12:20
URI: http://d-scholarship.pitt.edu/id/eprint/45851

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