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Engineered EGF-A Peptides with Improved Affinity for Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)
Benjamin J Tombling1, Carmen Lammi2, Nicole Lawrence1
1Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland 4072, Australia.
ACS Chemical Biology
|January 29, 2021
Summary
Researchers engineered a protein domain (EGF-A) to better bind PCSK9, a target for lowering cholesterol. The improved analogue, TEX-S2_03, shows significantly higher affinity and therapeutic potential for hypercholesterolemia.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- The epidermal growth-factor-like domain A (EGF-A) is a potential therapeutic target for inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9).
- Current EGF-A has suboptimal affinity for PCSK9, limiting its clinical application for hypercholesterolemia treatment.
Purpose of the Study:
- To engineer EGF-A analogues with enhanced affinity for PCSK9 using phage display.
- To develop improved therapeutic leads for hypercholesterolemia by optimizing EGF-A interactions with PCSK9.
Main Methods:
- Phage display was employed to identify EGF-A analogues with extended bioactive segments.
- Thermodynamic binding analysis and functional cell assays were used to characterize the binding affinity and efficacy of the identified analogues.
Main Results:
- The engineered analogue TEX-S2_03 exhibited approximately 130-fold increased affinity for PCSK9 compared to the parent EGF-A domain.
- TEX-S2_03 demonstrated reduced calcium dependency for PCSK9 binding and improved activity in competition binding and cell-based assays.
- Enhanced binding was enthalpically driven, suggesting favorable interactions between the extended segment of TEX-S2_03 and the PCSK9 surface.
Conclusions:
- TEX-S2_03 is a potent therapeutic lead for hypercholesterolemia, showing significantly improved PCSK9 inhibition.
- The strategy for engineering EGF-like domains offers a broadly applicable approach for developing novel therapeutics targeting protein-protein interactions.
