Abstract |
Four "one-bead one-compound" (OBOC) combinatorial libraries were designed, synthesized, and screened against MDA-MB-231 breast cancer cells. A novel cyclic peptide 1 (LXY1) with high binding specificity to alpha3 integrin was identified. Molecular interactions between alpha3 integrin and 1 were characterized by using a series of K562 cells transfected with various mutant alpha3 integrins. Using analytic flow cytometry, the binding affinity (K(d)) of 1 to alpha3 integrin on MDA-MB-231 breast cancer cells was determined to be approximately 0.4 microM. Based on the established structure-activity relationship (SAR) study, two highly focused cyclic peptide libraries were further designed, synthesized, and screened against MDA-MB-231 breast cancer cells under stringent conditions. A novel cyclic peptide 2 (LXY3) with a high binding affinity (IC(50) = 57 nM) was identified. Moreover, the targeting efficiency and specificity of 2 to the breast adenocarcinoma tumors in mouse xenografts were further confirmed by in vivo and ex vivo near-infrared fluorescence optical imaging.
|
Authors | Nianhuan Yao, Wenwu Xiao, Xiaobing Wang, Jan Marik, See Hyoung Park, Yoshikazu Takada, Kit S Lam |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 52
Issue 1
Pg. 126-33
(Jan 08 2009)
ISSN: 1520-4804 [Electronic] United States |
PMID | 19055415
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
|
Chemical References |
- Integrin alpha3
- Ligands
- Peptides
|
Topics |
- Animals
- Biomimetic Materials
(chemical synthesis, chemistry, metabolism)
- Biotinylation
- Breast Neoplasms
(metabolism, pathology)
- Cell Line, Tumor
- Combinatorial Chemistry Techniques
- Databases, Protein
- Drug Design
- Female
- Humans
- Integrin alpha3
(metabolism)
- Ligands
- Magnetic Resonance Spectroscopy
- Mice
- Mice, Nude
- Molecular Structure
- Peptides
(chemical synthesis, chemistry, metabolism)
- Structure-Activity Relationship
- Substrate Specificity
- Xenograft Model Antitumor Assays
|