Peptides Targeting GPCRs

Peptides are excellent targeting vectors for developing cancer therapies, through their ability to bind with high affinity to receptors found on cancer cells. Radiolabelled peptides provide a means of imaging or treating cancer tumours through the addition of a short-lived radioisotope. Our research team develops chemical technology for the discovery of cancer-targeted peptides and develops cancer theranostics, compounds that can be both therapeutic and diagnostic. Our research looks at a number of G protein-coupled receptors such as the ghrelin receptor, PAR2, CXCR4, and others. Team members in the Luyt Group design, synthesize and evaluate novel peptide-based agents, gaining skills in synthetic chemistry, medicinal chemistry and radiochemistry.

Ghrelin receptor (GHSR)

The natural ligand for the ghrelin receptor (GHSR) is the peptide ghrelin, consisting of a 28 amino acid sequence and a unique post-translational acylation, with a short biological half-life of only a few minutes. We have created truncated and stabilized analogues of ghrelin for imaging, providing fluorine-labelled, metal-labelled and fluorescent dye-labelled analogues. Peptide analogues for ghrelin(1-8) have been discovered with sub-nanomolar affinity, significantly improved as compared to the natural ghrelin(1-28), with additional modifications resulting in improved stability from proteolytic degradation.

PAR2 

Protease-activated receptor 2 (PAR2) is a GPCR activated by serine protease cleavage of its N-terminus, exposing a tethered ligand. Synthetic peptidomimetics mimicking this ligand show significantly improved PAR2 efficacy over the native peptide. Through structure-activity relationship studies (SAR), we modified the C-terminal region of lead peptidomimetics to incorporate a fluorescent dye, a fluorine-18-compatible prosthetic group, or a gallium-68 chelator. The resulting imaging agents exhibit low nanomolar EC50 values, and the fluorescent agent demonstrates strong uptake in cancer cell lines and patient-derived organoids.

Nanomaterials for Biomedical Applications

Nanoparticles offer a means for cancer targeting with multi-modal diagnostic or therapeutic biomedical applications. Peptides can create a wide array of nanoarchitectures, ranging from nanospheres, nanotubes, to nanofibers and others. We have created cyclic peptide nanotubes, as cancer-targeting imaging agents. Using peptides as the nano-forming scaffold, provides a biomaterial with enhanced solubility and biocompatibility. We are now designing and synthesizing peptide-based nanobiomaterials for cancer imaging, with fluorescent and radioisotope imaging capabilities.

Metal-Containing Cyclic Peptides 

Our lab discovers innovative strategies to create diverse peptide structures for imaging agent design, pharmaceuticals and biomaterials. The focus of this work is on cyclic peptides, a class of biomolecules with extraordinary capabilities for biological interactions and stability. Through melding our peptide chemistry and coordination chemistry knowledge, we are developing chemical technology for the creation of metal-containing cyclic peptide entities. Our focus is on Ga, Tc, Re, Pb and Ac, all of which are relevant as radiometals for theranostic applications.