Grant: Discovery Grants Program - Individual

This NSERC Discovery grant proposal seeks to develop diverse peptide structures resulting in innovative strategies for imaging agent design, pharmaceuticals and biomaterials. The focus is on cyclic peptides, a class of biomolecules with extraordinary capabilities for biological interactions and stability. There is increasing interest and demand for moving chemical technology forward in the creation of cyclic peptide entities. In this Discovery grant application, we propose three novel approaches for advancing cyclic peptide chemistry, coalescing around the long-term vision of developing new chemical technology for creating cyclic peptide imaging agents and biomaterials. Specific short-term objectives that will be pursued in this research program over the next 5 years are as follows: Objective 1. To discover peptide nanostructures for imaging. Nanoparticles are incredibly small entities capable of playing a multi-functional role. The vision for this aim is to create peptide nanotubes as a biomaterial scaffold, based upon a cyclic peptide framework, with modifications for receptor targeting, pharmacokinetic refinement and imaging components. This will provide great flexibility in designing nanostructures for medical and other applications. Significance: The discovery of a platform technology for creating biocompatible nanostructures as targeted imaging agents. Objective 2. To create radiometal-stapled peptides. Peptides are short sections of a protein and they don't always maintain the shape that is required for biological activity. Peptide staples are a way to cyclize a peptide and create an alpha-helical structure, which better mimics the natural structure found in a protein. Our vision is to develop peptide stapling methods where uniquely, the staple consists of a metal complex, resulting in the formation of biologically relevant peptide conformations. Significance: We will discover an innovative approach for incorporating radiometals within peptide structures such that they mimic natural secondary structure conformations. Objective 3. To establish bivalent targeting methods for GPCR dimers. G protein-coupled receptor (GPCR) dimerization has been discovered to play important physiological roles, yet there is limited knowledge about the implications to biological function and human health. We propose to discover bivalent peptide ligands targeting GPCR heterodimers, developing chemical tools to understand the relevance of these receptor interactions. Significance: The creation of novel peptide-based chemical tools for exploring, imaging and evaluating GPCR dimerization. Through these three objectives, we will discover novel chemical approaches to the design, preparation and application of cyclic peptides. These discoveries will lead to improved approaches to developing radiopharmaceuticals for imaging or therapy, and for biomaterials for use in imaging and drug delivery.