Sofia Legarreta
Fordham University
Enhancing Peptide Inhibitors of the EphB2 Receptor through N-Terminal and Tryptophan Modifications
Eph receptors are the largest family of receptor tyrosine kinases and initiate cell signaling processes through their interactions with ephrins. Overexpression of the EphB2 receptor was recently linked with the proliferation of gastrointestinal and esophageal cancers. Inhibiting EphB2 receptor signaling is therefore promising to reduce tumor growth in cancers in which EphB2 is upregulated. One method to reduce EphB2 receptor signaling is to use peptide-based inhibitors that block the EphB2 receptor’s interaction with ephrins. One such peptide, SNEW, was found to specifically inhibit the EphB2 receptor but with only moderate inhibitory potency. Analysis of the crystal structure of the EphB2 receptor interaction with SNEW indicated regions of the peptide that could be modified with nonnatural amino acids to improve potency, namely the N-terminus and central tryptophan residue. We synthesized and purified a small library of modified SNEW peptides and evaluated how different modifications affected each peptide’s ability to block EphB2 receptor interactions with ephrin B2. From this library, we identified several modified SNEW peptides with better potency than SNEW for inhibiting the EphB2 receptor’s interaction with ephrin B2. These peptides retained SNEW’s specificity for the EphB2 receptor and may offer a new peptide-based strategy to inhibit EphB2 receptor signaling to treat esophageal, gastrointestinal, and other cancers.
Eph receptors are the largest family of receptor tyrosine kinases and initiate cell signaling processes through their interactions with ephrins. Overexpression of the EphB2 receptor was recently linked with the proliferation of gastrointestinal and esophageal cancers. Inhibiting EphB2 receptor signaling is therefore promising to reduce tumor growth in cancers in which EphB2 is upregulated. One method to reduce EphB2 receptor signaling is to use peptide-based inhibitors that block the EphB2 receptor’s interaction with ephrins. One such peptide, SNEW, was found to specifically inhibit the EphB2 receptor but with only moderate inhibitory potency. Analysis of the crystal structure of the EphB2 receptor interaction with SNEW indicated regions of the peptide that could be modified with nonnatural amino acids to improve potency, namely the N-terminus and central tryptophan residue. We synthesized and purified a small library of modified SNEW peptides and evaluated how different modifications affected each peptide’s ability to block EphB2 receptor interactions with ephrin B2. From this library, we identified several modified SNEW peptides with better potency than SNEW for inhibiting the EphB2 receptor’s interaction with ephrin B2. These peptides retained SNEW’s specificity for the EphB2 receptor and may offer a new peptide-based strategy to inhibit EphB2 receptor signaling to treat esophageal, gastrointestinal, and other cancers.
