Therapeutic development of secreted peptides uncovered by Barcoded Ligand Sequencing

Secreted proteins and their surface receptors represent ~70% of FDA-approved drug targets, yet our understanding of protein-cell interaction networks remains fragmentary, and we cannot easily determine which proteins will strongly interact with a given cell type. To address this limitation, we developed Barcoded Ligand Sequencing (BLS) as a high-throughput platform for multiplexed measurement of thousands of ligand-cell interactions. By applying this novel discovery platform to primary neurons, we isolated a previously uncharacterized region of a neurodegeneration-associated propeptide as a high-affinity neuron-binding ligand. We now propose to employ BLS-related approaches to identify the exact relevant peptide species, characterize its effects in mice, and isolate its cognate cell surface receptor. These studies aim to validate the broad utility of the BLS screening approach for efficient discovery of disease-modifying peptides.