Protein-protein interactions (PPIs) are involved in many cellular processes, making them potential drug targets. Many of these interactions involve amino acid residues projecting off of an a-helix. Small molecules have been designed to mimic short amino acid sequences important for binding to target proteins. Many of these small molecules mimic only the hydrophobic face of the a-helix, possibly excluding important interactions arising from polar residues. The Orchard Group has designed novel, amphiphilic, small-molecule a-helix mimics capable of mimicking consecutive amino acid residues on both faces of the helix for treatment of various diseases, such as Human Papillomavirus (HPV) infection. HPV is a small DNA virus that infects epithelial cells. The E6 oncogenic protein in HPV allows for survival of infected cells by binding to the human protein E6AP. Binding allows for degradation of p53, a tumor suppressing protein. Inhibition of E6 should allow for apoptosis of infected cells, clearing the infection in a non-invasive way. Our proposed library of potential a-helix mimetics has been rationally designed with the aid of Molsoft ICM Pro software, and synthesis of these compounds is underway. Herein, we present promising docking results and our proposed synthetic route toward a small subset of compounds capable of mimicking 4 of the 5 residues known to be important for E6 binding. Once synthesis is complete, compounds will be tested for their ability to cause apoptosis in infected cells as well as their ability to specifically inhibit the E6-E6AP interaction.

New α-helix mimetics targeting the E6 protein in the human papillomavirus

253rd National Meeting (2017)

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