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University of California Davis Cancer Center, Division of Hematology and Oncology, and Department of Internal Medicine, University of California Davis, Sacramento, California

Requests for reprints: Kit S. Lam, Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis, 4501 X Street, Sacramento, CA 95817. Phone: 916-734-8012. E-mail: kit.lam{at}ucdmc.ucdavis.edu

Using "one-bead one-compound" combinatorial chemistry technology, we generated random peptide libraries containing millions of 90 µm TentaGel beads, each with its own unique amino acid sequence. A cyclic random 8-mer library was screened with CAOV-3 (a human ovarian adenocarcinoma cell line) and beads with a unique ligand that bind to the cell surface receptors were coated by one or more layers of cells. These positive beads were isolated, stripped, and microsequenced. Several peptide motifs were identified from these screenings, some of which were novel and unique, e.g., cDGX₄GX₆X₇c. Structure-activity relationship studies of this peptide revealed that the L-aspartate residue at position 2, the two glycines at positions 3 and 5, and the two D-cysteines at the amino and COOH terminus are critical for activity. In addition, a hydrophobic residue was preferred at position X₄, whereas amino acids at positions X₆ and X₇ were more variable. Binding of this peptide to a number of different cancer cell lines and normal cells was also determined and we observed that peptides with this motif bound preferentially to three other human ovarian cancer cell lines (ES-2, SKOV-3, and OVCAR-3) as well as a human glioblastoma cancer cell line (A172). Structural analysis of the peptides using high-resolution nuclear magnetic resonance spectroscopy revealed strong conformational similarity among all peptides with cX₁GX₄GX₆X₇c motif. Blocking study with a panel of anti-integrin antibodies strongly suggests 3 integrin present on these ovarian adenocarcinoma cells is the target receptor for this peptide.

Key Words: Peptides • Ovarian cancer • Integrin • combinatorial chemistry

Grant support: This work was funded by R33 CA89706 (NIH, National Cancer Institute), 00-00764V-0133 (California Cancer Research Program), 5-T32-RR07038 (NIH training grant), and a Landgraf Cancer Research Award.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ (http://alces.med.umn.edu).

² Manuscript in preparation.

Received 1/26/05; revised 3/ 8/05; accepted 3/21/05.