Development of Peptide Antagonists of Chemokine Receptors Involved in Breast Cancer Metastasis
Abstract
In two separate reports, breast cancer cells were shown to express functionally active chemokine receptors which may promote metastasis, and an anti-human CXCR4 chemokine receptor monoclonal antibody was found to reduce the level of lung metastasis by 61-68 percent. Based on these findings supporting the role for chemokine ligand-receptor interactions in promoting metastasis of breast cancer, we develop small molecule antagonists to CXCR4. This was accomplished by screening in a competitive assay synthetic combinatorial libraries (SCLs) made up of D-amino acid peptides for their ability to antagonize CXCR4 receptor function using HeLa cells and PBMC cells (used as standard), and breast cancer cells (MDA-MB-231, known to express CXCR4), and a monoclonal antibody anti-CXCR4 known to block chemotaxis induced by CXCL12 (formerly known as SDF1-a). The SCL approach, particularly when generated in a positional scanning (PS) format, allows the direct identification of the key residue(s) of active peptide sequence(s) from the library screening. Following the screening of a library, candidate sequences were synthesized and their inhibitory activity on the binding of anti-CXCR4 antibody was evaluated as well as their ability to abrogate the migratory response of cells induced by SDF-1a.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2004
- Accession Number
- ADA432047
Entities
People
- Sylvie E. Blondelle