Rational Design of Peptide Binders Targeting Prominin-1 and Sortilin for Molecular Sensing Applications

High Resolution Image Download MS PowerPoint Slide Prominin-1 (CD133) and sortilin are two clinically important biomarkers that have been associated with multiple types of cancer. Designing molecules targeting these biomarkers is highly useful for both detection and targeted treatment of cancer. Current detection strategies for these biomarkers primarily rely on receptor-specific antibodies. However, antibodies have several limitations, including high sensitivity to glycosylation in prominin-1, poor tumor penetration, and limited suitability for a broad range of biomolecular assays. These limitations highlight the need for alternative targeting molecules, such as peptides. This study employs a peptide design approach based on residue-level binding for the rational design of peptides targeting prominin-1 and sortilin. This approach is based on identifying the amino acids with the highest predicted affinities toward the receptor and combining the strongest binding amino acids to create peptide sequences. Initially, candidate peptides with docking scores less than −8 kcal/mol were screened using molecular docking, and the binding stability of these peptides was verified by using molecular dynamics simulations. Preliminary experimental validation via biolayer interferometry indicated that these peptides bind to prominin-1 and sortilin with micromolar-level affinities. While the binding behavior of sortilin-targeting peptides suggested some heterogeneous binding, the overall binding behavior was consistent with micromolar-level affinities. This approach provides a promising method for developing peptide binders targeting critical biomarkers, such as prominin-1 and sortilin.