Dr. Ross Cheloha
Title: Connecting peptides and antibodies to probe cell surface receptors
Bio:
Dr. Ross Cheloha is a Stadtman Tenure Track Investigator at the National Institutes of Health in the National Institute of Diabetes, Digestive, and Kidney Diseases. He works on the development of new tools to study G protein-coupled receptors, with a focus on peptide chemistry, antibody engineering, and bioconjugation. He leads a group of postbaccalaureate and postdoctoral scientists focused on the development of antibody-ligand conjugates to uncover new biological mechanisms and outline novel paths towards therapeutic development.
Ross conducted his Ph.D. in the Department of Chemistry at the University of Wisconsin in the lab of Prof. Sam Gellman, where he developed α/β-peptide analogues of parathyroid hormone that possessed specialized properties. He did his postdoctoral work at MIT and Harvard Medical School in the lab of Prof. Hidde Ploegh, where he applied single domain antibody conjugates to interrogate cell biology and immunology. He is passionate leveraging approaches from disparate fields to provide tools to address vexing scientific questions.
Abstract:
G protein-coupled receptors (GPCRs) mediate responses to an enormous array of signaling molecules that control nuanced and essential biological processes. Understanding how different signaling molecules cause variable responses crucial for designing therapeutics. Because of the complexity of the GPCR-ligand network, new tools are needed to disentangle receptor function. To address these needs, we have developed a new toolbox of compounds that consist of synthetic GPCR ligands linked with antibodies or antibody fragments (nanobodies). A combination of methods including synthetic chemistry, protein expression and engineering, and enzyme-mediated ligation enables the preparation of homogenous ligand-antibody conjugates. These conjugates exhibit several useful properties including strong signaling potency, in vivo activity, high receptor subtype specificity, and striking pathway specific signaling (biased agonism) properties. Recent evidence suggests that antibody-ligand conjugates can act across two receptor protomers co-expressed in the same cell to enable “logic-gated” receptor activation. Collectively, this platform offers the opportunity for the development of new ligands with favorable properties to be used as mechanistic tools to illuminate aspects of GPCR function difficult to address with more traditional approaches.
Faculty Host: Prof. Sam Gellman