A Cyclic Peptide Inhibitor of HIF-1 Heterodimerization That Inhibits Hypoxia Signaling in Cancer Cells
| Autor: | Elena Miranda, Ali Tavassoli, Paul A. Townsend, Keith R. Fox, Suzanne A. Eccles, William Court, Franciane Hoakwie, F. Cuda, Abigail L. Male, Ida Karin Nordgren, Graham Packham, Charlotte E. Lawrence |
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| Rok vydání: | 2013 |
| Předmět: |
Gene isoform
Hypoxia-Inducible Factor 1 Aryl hydrocarbon receptor nuclear translocator Peptides Cyclic Biochemistry Article Catalysis Structure-Activity Relationship Colloid and Surface Chemistry Transcription (biology) Cell Line Tumor Humans Hypoxia Transcription factor Dose-Response Relationship Drug Chemistry Aryl Hydrocarbon Receptor Nuclear Translocator General Chemistry Hypoxia-Inducible Factor 1 alpha Subunit Molecular biology Cell biology Cell culture Cancer cell MCF-7 Cells Signal transduction Signal Transduction |
| Zdroj: | Journal of the American Chemical Society |
| ISSN: | 1520-5126 0002-7863 |
| DOI: | 10.1021/ja402993u |
| Popis: | Hypoxia inducible factor-1 (HIF-1) is a heterodimeric transcription factor that acts as the master regulator of cellular response to reduced oxygen levels, thus playing a key role in the adaptation, survival and progression of tumors. Here we report cyclo-CLLFVY, identified from a library of 3.2 million cyclic hexapeptides using a genetically encoded high-throughput screening platform, as an inhibitor of the HIF-1α/HIF-1β protein-protein interaction in vitro and in cells. The identified compound inhibits HIF-1 dimerization and transcription activity by binding to the PAS-B domain of HIF-1α, reducing HIF-1-mediated hypoxia response signaling in a variety of cell lines, without affecting the function of the closely related HIF-2 isoform. The reported cyclic peptide demonstrates the utility of our high-throughput screening platform for the identification of protein-protein interaction inhibitors, and forms the starting point for the development of HIF-1 targeted cancer therapeutics. |
| Databáze: | OpenAIRE |
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