Improving the potency of biomaterials for tissue growth

In recent years, it has been shown that synthetic biomaterials are not optimal supports for tissue
growth due to their lack of intrinsic biochemical signalling potential. To improve the biological potency
of these biomaterials and increase the reach of tissue engineering, key signalling proteins can be
attached. However, when these proteins are attached via non-specific conjugation chemistries, they
suffer a drastic loss of activity. There is therefore a need for site-selective approaches for protein-
biomaterial conjugation.
In this PhD, ligand-directed chemistry was studied to achieve this goal, with two new approaches to
achieve site selective modification of proteins without the need for protein engineering. The first
approach was based on using peptides as protein-binding ligands, while the second approach was
based on the use of 2-pyridinecarboxaldehydes as N-terminal targeting ligands.
This thesis will first introduce the peptide approach in Chapter 2, with details of the synthesis and
modification of the peptides required, then will focus in Chapter 3 on the binding of these modified
probes to their protein of interest. In Chapter 4, the use of these binding peptides for the formation
of ligand-directed probes will be discussed. Chapter 5 will develop similar chemistry on 2-
pyridinecarboxaldehydes, and finally Chapter 6 will describe the results using these two types of
probes for the modification of proteins.
Our results demonstrate that we can achieve site-selective modification of model proteins,
representing the first traceless modification of protein using pyridinium oxime and N-acyl-N-
sulphonamide (PyOx/NASA) system on a peptide in a traceless manner. With more optimization still
needed, these preliminary results are important for the biomedical field in which protein-biomaterial
conjugation is key for the formation of in-vitro tissue models for the study of various disease such as
myocardial infarction, diabetes, and osteoarthritis.