Date of Award

6-26-2026

Date Published

August 2026

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

Robert Doyle

Subject Categories

Chemistry | Physical Sciences and Mathematics

Abstract

The Doyle group has coined the term ‘corrination’ to describe the conjugate modification of a peptide, protein, small molecule, or radionuclide with a corrin ring-containing molecule such as cobalamin, also known as vitamin B12 (B12), or cobinamides. By exploiting the innate chemico-physical properties of corrin ring-containing compounds, both in general and specifically via the innate dietary B12 uptake pathway in mammals, corrination has been explored for drug development and targeted/localized delivery of probes and therapeutics. Most recently, it is in the field of peptide-based therapeutics that corrination is generating significant interest, no doubt driven in part by the recent successes of peptide-based pharmaceuticals such as the glucagon-like peptide-1 receptor (GLP-1R) agonists semaglutide (Ozempic) and tirzepatide (Zepbound) which are used to treat diabetes and/or obesity. Peptide-based drugs possess several limitations that restrict their clinical application, including poor solubility and stability, low oral bioavailability, and negative side effects often due to drug distribution. In the case of GLP-1R agonists for example, negative side effects such as inhibition of gastric mobility and nausea are the main drivers in patient discontinuation of medication. Therefore, methods must be developed to address these issues without affecting the peptide's functionality. Herein, I describe the design and synthetic approaches to peptide corrination, along with in vitro and in vivo biological evaluations to 1) mitigate peptide aggregation, 2) mitigate CNS-associated side effects in tumor bearing rats, 3) enable dose-dependent ocular delivery upon topical administration and 4) facilitate in utero delivery of oxytocin, which corresponds to Chapters 2-5, respectively. Chapter 6 focuses on work outside the corrination space with highlights in the discovery of natural peptides and de novo protein binding design. This work yielded novel, functional peptide-based conjugate therapeutics with enhanced solubility, stability, and targeted localization, thereby reducing off-target side effects while maintaining key in vivo target effects.

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