Dysregulation of receptor recycling is involved in solid tumor invasion and metastasis. Long-loop endocytic recycling uses Eps15-homology (EH) domain-containing proteins to traffic receptors back to the cell surface. To date, there are no known pharmacological inhibitors specific to long-loop endocytic recycling. EH domain-containing proteins such as EHD1 are critical for long-loop recycling, and inhibitors of these proteins represent an attractive way to slow cancer growth. The Kritzer lab previously identified a moderate inhibitor of the EH domain of EHD1 (K<sub>d</sub> = 3.1 μM) via a diversity-oriented approach utilizing thioether-stapled peptides. While these stapled peptides represent the most potent inhibitors of EHD1-EH to date, they could be improved in terms of potency, selectivity, and cell permeability. We have designed a novel class of stapled peptides that make use of mercaptoproline derivatives for peptide stapling. Due to its constrained nature, mercaptoproline staples will provide additional rigidity, which we hypothesize will improve both affinity and cell penetration. Herein, we describe the synthesis and evaluation of mercaptoproline-stapled peptides. Ultimately, improved EHD1 inhibitors will aid in further understanding long-loop recycling and EHD1’s roles in cancer progression and invasion.

Using mercaptoproline-stapling to improve the biological activity, selectivity, and cell permeability of constrained peptides

256th National Meeting (2018)

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