Thioether side chain cyclization for helical peptide formation: inhibitors of estrogen receptor–coactivator interactions

Abstract

Cystine, lanthionine, and cystathionine containing cyclic peptides incorporating the signature nuclear receptor (NR) box (LXXLL) motif have been synthesized and the abilities of these peptides to inhibit estrogen receptor (ER)-coactivator interactions have been determined. We found that helicity of these peptides directly correlated with their bioactivity. Cystathionine proved to be a redox-stable, isosteric replacement for the cystine disulfide. Cystathionine containing peptide 3 showed higher helical character and a lower inhibition constant (Ki, 7 nm) when compared with its cystine counterpart.

Molecular Basis of Agonistic Activity of ERα17p, a Synthetic Peptide Corresponding to a Sequence Located at the N-Terminal Part of the Estrogen Receptor αLigand Binding Domain

“…specificity of action. However, like most LxxLL-containing peptide mimics (called now PERMs [67,71,74]), ERα17p acts at relatively high concentration (IC50 ≈ 5 µM [13]) hardly appropriate for therapeutic applications. Besides, its growth promoting activity on ERα-positive cells precludes its potential use in women with high risk of breast cancer development.…”

Trophic effect in MCF-7 cells of ERα17p, a peptide corresponding to a platform regulatory motif of the estrogen receptor α—Underlying mechanisms

“…[10] for review). Indeed, a few of such peptides, as well as some non-peptidic mimics -called PERMs for "peptidomimetic estrogen receptor modulators" [11] or CBIs for "coactivator binding inhibitors" [12] -have been shown to modulate ER␣ activity by interacting with the receptor AF-2 domain [11][12][13][14][15][16][17][18][19].…”

Discovery of Small Molecule Inhibitors of the Interaction of the Thyroid Hormone Receptor with Transcriptional Coregulators

“…A combinatorial approach discovered novel ␣-helical proteomimetics that could selectively inhibit the interaction between coactivators and TR or the estrogen receptor (ER), with selectivity between ER isoforms ER␣ and ER␤ (26). A similar approach, using disulfide bridges to constrain peptides, resulted in selective ER␣ coactivator inhibitor with a K d of 25 nM (27,28). A report identifying a small molecule capable of inhibiting the interaction of a NR and its coactivator was published recently (29).…”