Engineered EGF-A Peptides with Improved Affinity for Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)

The epidermal growth-factor-like domain A (EGF-A) of the low-density lipoprotein (LDL) receptor is a promising lead for therapeutic inhibition proprotein convertase subtilisin/kexin type 9 (PCSK9). However, clinical potential EGF-A limited by its suboptimal affinity PCSK9. Here, we use phage display to identify analogues with extended bioactive segments that have improved most potent analogue, TEX-S2_03, demonstrated ?130-fold over parent and had reduced calcium dependency efficient PCSK9 binding. Thermodynamic binding analysis suggests TEX-S2_03 enthalpically driven, indicating favorable interactions are formed between segment surface. resulted in increased activity competition assays more restoration LDL levels clearance extracellular cholesterol functional cell assays. These results confirm treating hypercholesterolemia. Many EGF-like domains involved disease-related protein-protein interactions; therefore, our strategy engineering has be broadly implemented EGF-based drug design.