Thioether side chain cyclization for helical peptide formation: inhibitors of estrogen receptor-coactivator interactions.
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.
Galande
A K
AK
Department of Chemistry and the Institute for Molecular Diversity and Drug Design, University of Louisville, Louisville, KY, USA.
Bramlett
K S
KS
Burris
T P
TP
Wittliff
J L
JL
Spatola
A F
AF
D020816:Amino Acid Motifs; D000603:Amino Acids, Sulfur / Q000737:chemistry*; D001667:Binding, Competitive; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism*; D013440:Sulfides / Q000737:chemistry* / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism
D000603:Amino Acids, Sulfur; D009842:Oligopeptides; D010456:Peptides, Cyclic; D011960:Receptors, Estrogen; D013440:Sulfides; D014157:Transcription Factors