Peptide Brush Polymers: Theory and Synthesis for Functional Design

Oligonucleotides, oligosaccharides, and oligopeptides have shown tremendous potential as therapeutics and as tools for manipulating cells in culture for basic chemical biology studies. However, this promise has been consistently compromised by natural digestion processes and barriers that are prevalent in cells and tissues. These digestion processes mean that these biomolecules suffer from very short half-lives upon systemic (intravenous or oral) delivery and are degraded or excluded entirely from cells. These are evolutionarily beneficial barriers for healthy tissues, not wanting to uptake foreign biological molecules, and the fact that these biomolecules serve as sources of building blocks for cell/tissue growth. That is, in using these molecules we are trying to make functional molecules out of that which we normally regard as food. In addition to degradation, or resistance to cellular uptake, they can be low molecular weight as individual strands, a feature contributing to rapid clearance when administered systemically. In the proposed work, we will focus on the development of polymer scaffolds that are capable of displaying peptides at exceptionally high-density enabling resistance to degradation, while maintaining their bioactivity. These materials were a serendipitous discovery, for which we now propose an in depth theoretical and experimental analysis of mechanism and generality. Peptides are particularly exciting targets, ripe for development with new delivery methods, because there are millions of sequences readily derived from bioactive or important portions of known proteins. However, very few (< 60) peptide-based drugs are used clinically, and the majority of these are for metabolic disorders of the same class. In particular, diabetes type 1 and type 2, account for more than 30 of the approved peptide-drugs, where tremendous effort has been expended to increase and control circulatory half-life following systemic administration.