Development of Novel Peptide Inhibitors of the Estrogen Receptor
Abstract
The goal of this project was to develop short peptides derived from the sequence of the human estrogen receptor that might serve as a novel class of receptor antagonists. By interacting with the dimerization motif of this protein, these peptides were intended to interfere with subunit dimerization and therefore to disrupt the DNA-binding activity of this key regulatory factor. Peptides were purchased and screened for their ability to interfere with the DNA-binding ability of this receptor using an in vitro gel mobility shift assay. Five peptides were identified that specifically and reproducibly disrupted DNA-binding. Their inhibition was shown to be concentration dependent. These results were complemented by chemical mutagenesis experiments that identified two residues falling within regions defined by the inhibitory peptides (Ala505 and Leu511) whose mutation also interfered with DNA binding. These data are discussed in the context of recent information detailing the X-Ray crystal structure of the hormone-binding domain of the estrogen receptor. Experiments were also undertaken to test the transcriptional inhibitory activity of these active peptides in a transient transfection system. This ultimately proved unsuccessful due to difficulties in achieving efficient peptide uptake by cultured cells. The promising preliminary results from this work supported the filing of an invention disclosure that is currently under consideration for further development.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 1997
- Accession Number
- ADB240174
Entities
People
- Richard J. Miksicek
Organizations
- State University of New York