Structure-Activity Relationships of Synthetic Peptide Inhibitors Targeting PCSK9-LDLR Protein-Protein Interaction

This study investigates structure-activity relationships of synthetic peptide inhibitors of the PCSK9-LDL receptor protein-protein interaction within the context of chemical biology and lipid biochemistry, an area of growing scientific importance given its implications for next-generation oral PCSK9 inhibitor development for LDL-C lowering in cardiovascular disease. Using surface plasmon resonance kinetics binding assays and LDL receptor functional rescue HepG2 cell assay, we examine competitive displacement of PCSK9 from its EGF-A domain binding site on the LDL receptor extracellular domain in 24 peptide inhibitor variants spanning linear, monocyclic, and bicyclic scaffolds drawn from biochemistry laboratory surface plasmon resonance and cell culture systems. Results indicate that bicyclic peptide scaffold Bcy-7 achieves PCSK9 binding affinity of Kd 4.8 nM and restores 84.2% LDL receptor surface expression in PCSK9-treated HepG2 cells, matching monoclonal antibody controls (p < 0.001), with 84.2% LDLR surface expression restoration as the primary quantitative benchmark. Concordance between primary and confirmatory measurement approaches exceeded 93%, validating the analytical framework. These findings contribute empirically to chemical biology and lipid biochemistry and carry actionable implications for the design of programs and policies targeting next-generation oral PCSK9 inhibitor development for LDL-C lowering in cardiovascular disease.