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Structural and Functional Mimicry of Disulfide-Rich Peptides

Cabalteja, Chino (2020) Structural and Functional Mimicry of Disulfide-Rich Peptides. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Disulfide-rich peptides have promising applications as bioactive agents, but their utility is attenuated by synthetic challenges and various pharmacological drawbacks including low proteolytic stability. Some of these limitations may be addressed by foldamers – sequence specific oligomers with a propensity to fold into discrete conformations. One established approach to the design of foldamer mimics of peptides with complex folds involves incorporation of unnatural building blocks at strategic sites within the natural sequence. Applied judiciously, these modifications can result in peptide variants with a heterogeneous backbone which can adopt complex native-like folds. These proteomimetics can also display augmented pharmacological properties including improved proteolytic resistance. This study demonstrates the application of this heterogeneous backbone substitution strategy to disulfide-rich peptides in the context of structural mimicry of a computationally designed miniprotein and explores the consequences of peptide backbone modification on the function of a bioactive peptide toxin. Lastly, this work delves into the experimental characterization of a series of model tripeptides for validation of a newly developed force field that can simulate artificial protein-like backbones.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Cabalteja, Chinoccc49@pitt.educcc49
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairHorne, W. Sethhorne@pitt.eduhorne
Committee MemberIshima, Riekoishima@pitt.eduishima
Committee MemberIslam, Kabirulkai27@pitt.edukai27
Committee MemberRobinson, Renãrena.as.robinson@vanderbilt.edu
Date: 16 September 2020
Defense Date: 10 September 2020
Approval Date: 20 January 2021
Submission Date: 17 September 2020
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 147
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Molecular Biophysics and Structural Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: peptide synthesis,peptide mimics,non-canonical amino acids
Date Deposited: 20 Jan 2021 18:19
Last Modified: 20 Jan 2021 18:19
URI: http://d-scholarship.pitt.edu/id/eprint/39749

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