title: Optimization of RGD-Containing Cyclic Peptides against αvβ3 Integrin.
abstract: We have previously reported the use of one-bead-one-compound (OBOC) combinatorial technology to develop a disulfide cyclic, Arg-Gly-Asp-containing octapeptide LXW7 (cGRGDdvc), that targets αvβ3 integrin with high affinity and specificity. αvβ3 integrin is known to be overexpressed in many cancers and in tumor vasculature, and it has been established as a cancer therapeutic target. To further optimize LXW7, we have performed systematic structure-activity relationship studies. On the basis of the results, two highly focused OBOC peptide libraries were designed, synthesized, and screened against αvβ3 integrin-transfected K562 cells. One of the best ligands, LXW64, was found to have 6.6-fold higher binding affinity than LXW7, and showed preferential binding to cells expressing αvβ3 integrin. In addition to binding strongly to U-87MG glioblastoma cells in vitro, LXW64 also targets U-87MG xenografts implanted in nude mice, indicating that it is an excellent vehicle for the delivery of cytotoxic payload to tumors and tumor blood vessels that overexpress αvβ3 integrin. Mol Cancer Ther; 15(2); 232-40. ©2015 AACR.
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis Cancer Center, Sacramento, California.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis Cancer Center, Sacramento, California.
authors.forename: Wenwu
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Department of Chemistry, University of Texas-Pan American, Edinburg, Texas.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis Cancer Center, Sacramento, California.
authors.forename: Leah
authors.initials: L
authors.lastname: Meza
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis Cancer Center, Sacramento, California.
authors.forename: Harry
authors.initials: H
authors.lastname: Tseng
authors.affiliation: Department of Dermatology, University of California Davis School of Medicine, Sacramento, California.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Takada
authors.affiliation: Department of Chemistry, University of California Davis, Davis, California.
authors.forename: James B
authors.initials: JB
authors.lastname: Ames
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis Cancer Center, Sacramento, California. kslam@ucdavis.edu.
authors.forename: Kit S
authors.initials: KS
authors.lastname: Lam
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D020650:Combinatorial Chemistry Techniques; D016503:Drug Delivery Systems / Q000379:methods*; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D020014:K562 Cells; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D039302:Integrin alphaVbeta3; D010456:Peptides, Cyclic