Stapled Peptides with γ-Methylated Hydrocarbon Chains for the Estrogen Receptor/Coactivator Interaction
“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 incor...
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Published in | Angewandte Chemie Vol. 128; no. 13; pp. 4324 - 4327 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English German |
Published |
Weinheim
Blackwell Publishing Ltd
18.03.2016
Wiley Subscription Services, Inc |
Subjects | |
Online Access | Get full text |
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Summary: | “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. |
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Bibliography: | American Association of Colleges of Pharmacy istex:E6B3C104D13EB586EBB27C45A25B2A7324DE836C NIH - No. P41-GM104601; No. T32 AT007533 Office of the NIH Director and the National Center for Complementary and Integrative Health ark:/67375/WNG-LB3PVNP1-D ArticleID:ANGE201510557 Searle Funds at The Chicago Community Trust University of Illinois Cancer Center NSF - No. MCA06N060 These authors contributed equally to this work. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0044-8249 1521-3757 |
DOI: | 10.1002/ange.201510557 |