Harmon, Thomas
(2024)
Backbone Modification on Three-Disulfide Miniproteins Using an Updated Proteomimetic
Toolbox: Oxidative Folding, Structural Analysis, and Biologically Pertinent Effects.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Incorporation of artificial residues to enhance the properties of peptides has long been a topic of interest for both fundamental and applied studies. Utilizing peptides or proteins for their advantages, such as tight binding and high specificity, while addressing their potential drawbacks, like limited bioavailability, has found increasing use in pharmaceutical industry in recent years. In this dissertation, I will describe research exploring how modifications to peptide backbones influence stability, structure, and function across various peptide and miniprotein systems. The research reported here is divided into four chapters: 1) Modifications to the peptide backbone in non-hairpin β-turns and their effects on the stability and folding of tertiary structures. This research completed the design optimization of proteomimetic analogues for the four most common structurally defined β-turns. 2) Comparative thermodynamic analysis of Aib and L-α-methyl amino acid replacements in α-helical peptides with complex folding, displaying the effect of chirality in α,α-dialkylated residues on helix stabilization. 3) Impact of diverse backbone alterations on disulfide bond formation in the cystine knot peptide, Ceratotoxin-I. While structural mimicry of the prototype was not achieved, this research further proves the complexities involved in the cystine knot motif, especially when compared to other three-disulfide peptides. 4) Proteomimetic variants of NZ2114: Enhancing proteolytic stability in antimicrobial peptides through backbone modifications. Through systematic substitution with artificial monomers, extensive resistance to trypsin hydrolysis and enhanced resistance to proteases generally was achieved, while precisely mimicking the structure and maintaining the bactericidal effect of the peptide. Together, these projects and their results further our understanding of backbone modification of peptides and exemplify their potential as a tool for proteomimetic design.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
20 December 2024 |
| Date Type: |
Publication |
| Defense Date: |
3 December 2024 |
| Approval Date: |
20 December 2024 |
| Submission Date: |
5 December 2024 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
293 |
| 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: |
Mimicry
Peptide
Backbone Modification
Antimicrobial
Helix Stabilization
Disulfide-Rich Peptides |
| Date Deposited: |
20 Dec 2024 14:24 |
| Last Modified: |
10 Apr 2025 14:37 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/47194 |
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