Text

theses

Many cellular pathways are dependent on receptor activation by proteins which have low stability. Recombinant growth factors and cytokines used to activate these pathways are expensive to produce and rapidly denature in solution. Short peptide sequences have been developed that are able to mimic the activity of various recombinant proteins. These mimetics frequently derive from sequences present within the native protein ligand and therefore retain the ability to bind to receptors. While peptides are advantageous with regard to their stability, they typically are unable to oligomerize and effectively cluster cellular receptors resulting in a weak cellular response. To overcome this problem, we seek to develop polymer-peptide conjugates that allow for the multivalent display of peptide binding units to receptors and enhance receptor oligomerization and potentiate the cellular response. For this study, we focus on developing mimetics of Vascular Endothelial Growth Factor (VEGF) and Erythropoietin (EPO). These proteins were selected as they have well defined pathways and receptor binding as well as characterized mimetic peptides. A library of 60 polymer-peptide conjugates differing in composition and peptide valency was developed for each of the target proteins. The conjugates were screened for bioactivity, revealing several that exhibited low levels of receptor activation.

ETD_10404

M.S.

Includes bibliographical references

doi:10.7282/t3-etem-2b12

ETD graduate