Stapled Peptides with γ-Methylated Hydrocarbon Chains for the Estrogen Receptor/Coactivator Interaction

• Published in: Angewandte Chemie Vol. 128; no. 13; pp. 4324 - 4327
• Main Authors: Speltz, Thomas E., Fanning, Sean W., Mayne, Christopher G., Fowler, Colin, Tajkhorshid, Emad, Greene, Geoffrey L., Moore, Terry W.
• Format: Journal Article
• Language: English; German
• Published: Weinheim Blackwell Publishing Ltd 18.03.2016; Wiley Subscription Services, Inc
• Subjects: Amino acid sequence; Amino acids; Aminosäuren; Chemistry; Conformation; Constraining; Crystallography; Estrogens; Isoleucine; Konformationsanalyse; Leucine; Molecular chains; Molecular dynamics; Pentane; Peptide; Peptides; Peptidmimetika; Receptors; Residues; Rezeptoren; Staples; Steroids
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201510557

“Stapled” peptides are typically designed to replace two non‐interacting residues with a constraining, olefinic staple. To mimic interacting leucine and isoleucine residues, we have created new amino acids that incorporate a methyl group in the γ‐position of the stapling amino acid S5. We have incorporated them into a sequence derived from steroid receptor coactivator 2, which interacts with estrogen receptor α. The best peptide (IC50=89 nm) replaces isoleucine 689 with an S‐γ‐methyl stapled amino acid, and has significantly higher affinity than unsubstituted peptides (390 and 760 nm). Through X‐ray crystallography and molecular dynamics studies, we show that the conformation taken up by the S‐γ‐methyl peptide minimizes the syn‐pentane interactions between the α‐ and γ‐methyl groups. Peptid‐Klammer: γ‐Verzweigte „klammernde” Aminosäuren wurden synthetisiert und in Peptide eingebaut, um hoch affine Inhibitoren der Östrogenrezeptor/Steroidrezeptor‐Coaktivator‐Wechselwirkung zu erhalten. Einige dieser Peptide waren effektiver als das nichtfunktionalisierte Peptid. Wie sich 1,5‐Wechselwirkungen auf die Peptidkonformation auswirken, wurde durch Circulardichroismus, Kristallographie und Moleküldynamik untersucht.