Structural Basis of Inhibition of ER alpha-Coactivator Interaction by High-Affinity N-Terminus Isoaspartic Acid Tethered Helical Peptides

Direct inhibition of the protein protein interaction of ER alpha and its endogenous coactivators with a cell permeable stabilized peptide may offer a novel, promising strategy for combating ER alpha positive breast cancers. Here, we report the co-crystal structure of a helical peptide stabilized by a N-terminal unnatural cross-linked aspartic acid (TD) in complex with the ER alpha ligand binding domain (LBD). We designed a series of peptides and peptide 6 that showed direct and high-affinity binding to ERa with selective antiproliferative activity in ER alpha positive breast cancer cells. The co-crystal structure of the TD-stabilized peptide 6 in complex with ER alpha LBD further demonstrates that it forms an alpha helical conformation and directly binds at the coactivator binding site of ER alpha. Further studies showed that peptide 6(w) could potently inhibit cellular ER alpha's transcriptional activity. This approach demonstrates the potential of TD stabilized peptides to modulate various intracellular disorders.