Design and Synthesis of Truncated EGF-A Peptides that Restore LDL-R Recycling in the Presence of PCSK9 In Vitro

Disrupting the binding interaction between proprotein convertase (PCSK9) and the epidermal growth factor-like domain A (EGF-A domain) in the low-density lipoprotein receptor (LDL-R) is a promising strategy to promote LDL-R recycling and thereby lower circulating cholesterol levels. In this study, truncated 26 amino acid EGF-A analogs were designed and synthesized, and their structures were analyzed in solution and in complex with PCSK9. The most potent peptide had an increased binding affinity for PCSK9 (KD = 0.6 μM) compared with wild-type EGF-A (KD = 1.2 μM), and the ability to increase LDL-R recycling in the presence of PCSK9 in a cell-based assay. •Structure-based design was used to identify inhibitors of the PCSK9/LDL-R complex•Small EGF-A-based inhibitors of PCSK9 were identified based on rational design•The peptides retained binding affinity as well as functional activity for PCSK9•The structure of an EGF-A-based inhibitor was determined in complex with PCSK9 Low-density lipoprotein (LDL) cholesterol contributes to an increased risk of cardiovascular disease. Schroeder et al. have designed an inhibitor of the circulating plasma protein PCSK9, which has the potential to lower cholesterol.