Investigation of Small Peptide Inhibitors on PD-1 PD-L1 Protein-Protein Interactions
Abstract
Cancer is a complex disease in which abnormal cells divide uncontrollably and invade body tissues, leading to eventual organ failure and death. These abnormal cells are able to grow and spread by evading recognition and destruction by the immune system through multiple mechanisms. Utilization of immune checkpoints, which are regulators of the immune system that prevent autoimmunity, is one such mechanism exploited by cancer cells. A specific immune checkpoint pathway involves tumor cells upregulating PD-L1 or programmed death ligand 1. When bound to its receptor PD-1, or programmed death protein 1, PD-L1 prevents the anti-tumor immune response normally responsible for clearing abnormal cells throughout the body. Within the past decade, a new class of drugs called immune checkpoint inhibitors have been developed to block this interaction and unleash the patient’s immune system on their tumor cells. While these drugs have seen promising results for some patients, there are still limitations that need to be overcome. Many of the existing cancer immunotherapies are in monoclonal antibody form and have problems with specificity, tissue penetration, route of administration, and are expensive to produce. In this study, we characterized and tested eight different small peptide inhibitors to the PD-1 PD-L1 pathway that were developed using protein painting, a novel technique used to identify specific hotspots within the binding interface. These small peptide inhibitors have the potential to be more specific than antibody therapies by exclusively targeting the protein-protein interface and could potentially be optimized to allow for oral administration. We also characterized various molecular dyes for future protein painting and introduced preliminary studies which optimize cell painting, a novel technique that uses molecular dyes on the surface of living cells to elucidate new drug targets and create whole cell “interactomes” between immune and target cell types.
Description
This thesis has been embargoed for 10 years. It will not be available until May 2028 at the earliest.
Keywords
PD-1, PD-L1, Small peptide inhibitors, Checkpoint inhibition, Immune checkpoints, Cancer immunotherapy