Author Type

Graduate Student

Date of Award

Summer 8-14-2026

Document Type

Dissertation

Publication Status

Version of Record

Submission Date

August 2026

Department

Chemistry and Biochemistry

College Granting Degree

Charles E. Schmidt College of Science

Department Granting Degree

Chemistry and Biochemistry

Degree Name

Doctor of Philosophy (PhD)

Thesis/Dissertation Advisor [Chair]

Stéphane Roche

Abstract

Peptide therapeutics have emerged as promising alternatives to monoclonal antibodies because of their smaller size, improved tissue penetration, and synthetic versatility. Yet their broader application is often limited by poor structural stability, rapid clearance, and reduced target residence times. This dissertation describes the design, synthesis, structural characterization, and biological evaluation of β-hairpin peptides as inhibitors of immune checkpoints and as peptide vaccine scaffolds while developing strategies to overcome these limitations. At first a series of antibody-derived β-hairpin peptides (mimics of complementary determining region heavy-chain 3: CDR-H3s) as covalent inhibitors of the PD-1/PD-L1 immune checkpoint were investigated. Electrophilic warheads were incorporated into lead peptide inhibitors to target solvent-accessible lysine residues on PD-1, and complementary mass spectrometric approaches were developed to characterize peptide-protein conjugation. In addition, the pharmacokinetic properties of CDR-H3 β-hairpin mimetics were evaluated through lipidation and albumin-binding strategies. Structural analysis confirmed retention of the β-hairpin fold, while serum stability, albumin-binding, and mouse pharmacokinetic studies demonstrated substantially prolonged systemic circulation and improved drug-like properties. Finally, cysteine residues were incorporated into β-hairpin scaffolds to study a templated cyclization strategy. Spectroscopic analyses demonstrated that preorganized scaffolds promote an efficient macrocyclization of long and flexible peptide loops (up to 16-mer) while preserving the native β-hairpin architecture, providing new design principles to create cyclic β-hairpin peptide therapeutics. These design principles were applied to peptide cancer vaccines targeting PD-1, HER2, and HER3 to mimic β-hairpin epitopes of a protein of interest. Structural characterization demonstrated that the short β-hairpin scaffolds can maintain epitope folding within larger vaccine constructs, supporting its application in future vaccine development. This work establishes β-hairpin peptides as a versatile platform for antibody CDR mimicry, covalent inhibition, pharmacokinetic optimization, and peptide vaccine design.

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