DOI
https://doi.org/10.25772/073Q-RB85
Defense Date
2019
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Chemistry
First Advisor
Matthew C. T. Hartman
Abstract
Peptides are emerging as promising therapeutics due to their inhibitory affinity towards protein-protein interactions (PPI). However, peptides have been limited mainly by their poor bio-stability and lack of cell permeability. Efforts to generate drug-like peptides have led to the development of macrocyclic peptides, which exhibit improved stability. Yet, most macrocyclic peptides still require the assistance of a cell penetrating peptide (CPP) for cellular entry.
High throughput technologies have been exceptional tools for the discovery of peptides to interrupt PPIs. This work details the recent advancements we have made to improve our high throughput technique, mRNA display, to yield more therapeutically relevant peptides to inhibit PPIs. Our advancements are focused on cell permeability, protease stability, and secondary structure for enhanced affinity.
Here we develop and optimize a cyclic CPP that can be included in future mRNA display libraries. We also tested the ability of our CPP to deliver an impermeable peptide cargo into cells. We rationally designed and tested linear and cyclic peptides to improve affinity to the BRCA1 protein. We used computational work to complement our experimental results for our CPPs and BRCA1 inhibitors. We examined peptides that arose from a library containing a mix of linear, monocyclic, and bicyclic peptides constructed using orthogonal cyclization chemistries. We rationally designed cyclic peptides and tested their affinity against Hsp70. We proposed a novel selection strategy to find optimal CPP motifs.
Rights
© Nicolas A. Abrigo
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-10-2019