Helix-stabilized cyclic peptides as selective inhibitors of steroid receptor–coactivator interactions
Open accessAbstract
The interaction between nuclear receptors and coactivators provides an arena for testing whether protein–protein interactions may be inhibited by small molecule drug candidates. We provide evidence that a short cyclic peptide, containing a copy of the LXXLL nuclear receptor box pentapeptide, binds tightly and selectively to estrogen receptor α. Furthermore, as shown by x-ray analysis, the disulfide-bridged nonapeptide, nonhelical in aqueous solutions, is able to adopt a quasihelical conformer while binding to the groove created by ligand attachment to estrogen receptor α. An i, i +3 linked analog, H-Lys-cyclo( d -Cys-Ile-Leu-Cys)-Arg-Leu-Leu-Gln–NH 2 (peptidomimetic estrogen receptor modulator 1), binds with a K i of 25 nM, significantly better than an i, i +4 bridged cyclic amide, as predicted by molecular modeling design criteria. The induction of helical character, effective binding, and receptor selectivity exhibited by this peptide analog provide strong support for this strategy. The stabilization of minimalist surface motifs may prove useful for the control of other macromolecular assemblies, especially when an amphiphilic helix is crucial for the strong binding interaction between two proteins.
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- Authors
- Leduc, A.-M., Trent, J. O., Wittliff, J. L., Bramlett, K. S., Briggs, S. L., Chirgadze, N. Y., Wang, Y., Burris, T. P., & Spatola, A. F.
- Affiliations
- University of Louisville (US)
- Departments of Chemistry, Medicine, and Biochemistry and Molecular Biology and the Institute for Molecular Diversity and Drug Design, and James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40292; and Lilly Research Laboratories, Indianapolis, IN 46285
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-09-17
- Volume
- 100
- Issue
- 20
- Pages
- 11273-11278
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC208747
- OpenAlex
- W2141267373
- Cited by
- 222
- References
- 46
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 7 · 2023: 3 · 2022: 5 · 2021: 9 · 2020: 9 · 2019: 11 · 2018: 11 · 2017: 6 · 2016: 18 · 2015: 11 · 2014: 14 · 2013: 13 · 2012: 13
- FWCI
- 3.45
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- cyclic peptides, estrogen receptor alpha, LXXLL motif, protein-protein interaction inhibitors, disulfide-bridged peptides, peptidomimetics, nuclear receptors, small molecule drug candidates
- MeSH terms
- Amino Acid Sequence, Circular Dichroism, Models, Molecular, Molecular Sequence Data, Peptides, Cyclic, Protein Conformation, Receptors, Steroid, Crystallography, X-Ray, Nuclear Magnetic Resonance, Biomolecular
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