Protein Chemical Synthesis Combined with Mirror-Image Phage Display Yields D-Peptide EGF Ligands that Block the EGF-EGFR Interaction
42 Pages Posted: 16 Apr 2019 Sneak Peek Status: Under ReviewMore...
EGFR, the receptor for epidermal growth factor (EGF), is arguably considered the most important therapeutic target in contemporary anticancer treatments. However, 20 years after the introduction of anti-EGFR drugs into the clinical setting, a number of severe drawbacks have been observed, namely low tumour penetration of monoclonal antibodies, acquisition of resistance to tyrosine-kinase inhibitors, and complete lack of efficacy in several types of cancer. Here, we report the design of a strategy to obtain all-D peptides directed to EGF instead of EGFR and we demonstrate their ability to block efficiently the EGF-EGFR interaction. We report an efficient chemical synthesis of the enantiomeric version of human EGF. Combined with the use of mirror-image phage display, this strategy has allowed us to discovery several protease-resistant peptides able to bind to EGF. Using alpha-screen technology we have demonstrated the capacity of the best peptide candidates to disrupt the EGF-EGFR interaction.
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