Chemical Biology Applications of Monocyclic Peptides

Peptides are one of the most promising platforms for drug development due to their biocompatibility, similarity, and diversity. Over the past few decades, it has been proven that peptides are practical tools in various therapeutic and diagnostic applications. Studies show that monocyclic peptides are capable of functioning as an effective alternative to complex molecules, such as antibodies or small molecules. In this dissertation, I describe projects that aimed at applying monocyclic peptides into the chemical biology field. The first chapter covers the screening procedures and results of a monocyclic peptide library in detail. Lipid A moiety was used as the screening target to demonstrate the therapeutic application of monocyclic peptides for LPS neutralization. Chapter 2 talks about the application of monocyclic peptides as imaging probes for protein activities in suspension cells. Digitonin, a cell membrane perforator will be introduced as the delivery mediator for the imaging probes. Analysis of AKT signaling activities on a single-cell level will be reported, including the demonstration of drug perturbation on the regulator proteins. Chapter 3 will cover the application of monocyclic peptides as molecular transporters. A small library of monocyclic peptides capable of penetrating the cell membrane will be introduced in this project. These hydroxyl-rich cycle peptides will demonstrate the diversity of cargo molecules into more than ten different cell lines. The mechanisms and fate of these monocyclic peptides will be discussed, providing a thorough explanation of the cell-penetrating process. The discovery of this novel group of peptides with non- positive charges can bring more insights into the cell-penetrating peptide field