Aldehyde and CyClick Cyclization Impacts on Peptide Cellular Permeability Restricted; Files Only

Abstract

Peptides and other hydrophobic molecules are considered viable candidates for drug discovery and biotherapeutic development due to their high affinity and specificity, but they suffer from poor cell penetration and stability. One potential solution to these issues has been the cyclization of peptides, but they also suffer from poor cellular permeability. A cyclization method known as CyClick has been developed in recent years that seek to overcome these issues. This method results in forming a 4-imidazolidinone moiety which introduces a ring to the peptide. A peptide’s ability to permeate the cell is due to varying structural motifs or conformations such as cyclization or the presence of certain functional groups. This study seeks to determine the effect of 4-imidazolidinone and aldehydes on peptide cell permeability. A series of cyclic peptides, peptide aldehydes, and CyClick peptides were synthesized and tagged with a chloroalkane tag to examine permeability. Using a recently developed chloroalkane penetration assay (CAPA), the permeability of these peptides was examined in cell models. The presence of both 4-imidazolidinone and aldehydes increased the permeability of peptides compared to cyclic and linear peptides not containing these structures. Further studies are being done to examine the impact of multiple aldehydes and their presence on cyclic peptides on cellular permeability. If these structures increase cellular permeability at a comparable rate to other permeability methods, then peptides aldehydes and CyClick-made aldehydes can be explored for future use in therapeutics and drug development.

Table of Contents

Table of Contents

Chapter 1: Introduction

Peptides as Drug Candidates

CyClick Chemistry and Purpose

Chapter 2: Materials and Methods

Synthesis of Linear Peptides

Synthesis of Fmoc-Alanine-Aldehyde

Synthesis of Aldehyde Resin

Synthesis of Aldehyde Linear Peptides

Synthesis of Macrocyclic Peptides

Synthesis of CyClick Peptides

Synthesis of Aldehyde Macrocyclic Peptides

Synthesis of Chloroalkane Tag

Deprotection of O-Allyl Glutamic Acid Containing Peptides

Coupling of Chloroalkane Tag and Peptide

Chloroalkane Penetration Assay

Chapter 3: Results and Discussion

Chapter 4: Conclusions and Future Directions

References

Supplemental Information

About this Honors Thesis

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School	Emory College
Department	Chemistry
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Molecular Chemistry, Biochemistry Chemistry, General
Keyword	4-imidazolidinone Cyclic Peptide CyClick Aldehydes Chloroalkane Penetration Assay Peptide Cellular Permeability Peptide Aldehydes
Committee Chair / Thesis Advisor	Monika Raj, Emory University
Committee Members	Tracy McGill, Emory University Frank McDonald, Emory University

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