A Novel Screen for Suppressors of Breast Tumor Cell Growth Using an Oriented Random Peptide Library Method to Identify Inhibitors of the ErbB2 Tyrosine Kinase.
Annual rept. 12 May 98-11 May 99
BETH ISRAEL DEACONESS MEDICAL CENTER BOSTON MA
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We are developing a novel degenerate cyclic peptide library selection method to identify potential peptide antagonists of the ErbB2 receptor tyrosine kinase. Since the aberrant activation of the ErbB2 receptor is believed to be involved in the genesis or progression of a significant proportion of human breast tumors, a cyclic peptide antagonist that binds selectively to the extracellular domain of ErbB2 could eventually be useful as an anti-breast cancer therapy. To identify potential antagonists, the extracellular ligand binding domain of the ErbB2 is immobilized on a column support, and used to affinity purify cyclic peptides from oriented random peptide libraries. The structures of oriented peptide libraries are based on the primary sequences of the twelve known peptide ligands for other members of the ErbB receptor family. Amino acid residues conserved in the known ligands are preserved, while those that vary are made degenerate at their corresponding positions in the library to select for high affinity binding to ErbB2. We anticipate that a high affinity synthetic peptide ligand for ErbB2 will be identified by this approach, which will then be assessed for its ability to act as an antagonist for the receptor.
- Anatomy and Physiology
- Medicine and Medical Research