This project outlines the development of macrocyclic peptide inhibitors of the Sonic Hedgehog (SHH)/Patched 1 interaction, a key protein-protein interaction (PPI) involved in the Hedgehog signaling pathway and in the progression of a number of human cancers. To achieve this goal, a macrocyclization strategy recently developed in our lab is applied to generate libraries of macrocyclic peptide mimetics of Hedgehog interacting protein, a natural inhibitor of SHH, in order to develop potent and selective SHH inhibitors. The macrocyclic peptides are generated through a spontaneous, post-translational reaction between a cysteine residue and a cysteine-reactive unnatural amino acid, O-(2-bromoethyl)-tyrosine (O2beY), which is incorporated using an engineered aminoacyl-tRNA synthetase/tRNA pair capable of suppressing an amber stop codon with O2beY. The utility of thioether-bridged macrocyclic inhibitors for the SHH/Patched 1 PPI as probes for better understanding of this pathway is discussed.

Thioether-bridged peptide macrocycles as inhibitors of the Sonic Hedgehog/patched 1 protein-protein interaction

253rd National Meeting (2017)

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