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Molecular Endocrinology 14 (12): 2010-2023
Copyright © 2000 by The Endocrine Society

Development of Peptide Antagonists That Target Estrogen Receptor ß-Coactivator Interactions

Julie M. Hall, Ching-yi Chang and Donald P. McDonnell

Department of Pharmacology and Cancer Biology Duke University Medical Center Durham, North Carolina 27710

The biological actions of estrogen are manifest through two genetically distinct estrogen receptors (ER{alpha} and ERß) that display nonidentical expression patterns in target tissues. The phenotypic alterations in response to estrogens in mice disrupted for either or both of these receptors are not identical, suggesting that each subtype plays a unique role in ER-action. However, the lack of subtype-specific agonists and antagonists has made it difficult to define the processes that are regulated by ER{alpha} and/or ERß. Previously, we have reported the identification and characterization of a series of LXXLL-containing peptide antagonists that block estrogen signaling by preventing the association of ER{alpha} with required coactivators. As expected, given the similarity of the coactivator binding pockets among nuclear receptors, most of the peptide antagonists identified inhibited the activity of multiple receptors. However, by altering sequences flanking the core LXXLL motif, some receptor selectivity was afforded. Building on this observation, we have screened combinatorial phage libraries, expressing peptides in the format X7LXXLLX7, for peptides that interact in a specific manner with ERß. Using this approach, a series of highly specific, potent peptide antagonists have been identified that efficiently inhibit ERß-mediated estrogen signaling when introduced into target cells. Interestingly, in cells where both ER subtypes were expressed, these ERß antagonists were capable of attenuating ER action, suggesting that ER{alpha} and ERß do indeed form functional heterodimeric complexes. We believe that suitably formulated versions of these peptides can be used to study ERß action in vitro and in vivo. In addition, the unanticipated specificity of the peptides identified should serve as an impetus to investigate the use of this approach to develop peptide antagonists of other nuclear receptors and unrelated transcription factors.




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