Structural development of stabilized helical peptides as inhibitors of estrogen receptor (ER)-mediated transcription.

Three types of stabilized helical peptides containing disulfide bonds, C-C cross-linked side chains, or α,α-disubstituted amino acids (2-aminoisobutyric acid (Aib)) were designed and synthesized as inhibitors of estrogen receptor (ER)-coactivator interactions. Furthermore, heptaarginine (R7)-conjugated versions of the peptides were prepared, and their effects on ER-mediated transcription were evaluated at the cellular level (in ER-positive T47D cells). Among them, the R7-conjugated peptides 11 and 12 downregulated the mRNA expression of pS2 (an ER-mediated gene whose expression is upregulated by 17β-estradiol) by 95% (at a dose of 10 μM) and 87% (at a dose of 3 μM), respectively.