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: Yan Wang, Wenwu Xiao, Yonghong Zhang, Leah Meza, Harry Tseng, Yoshikazu Takada, James B Ames, Kit S Lam
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 15 Issue 2 Pg. 232-40 (Feb 2016) ISSN: 1538-8514 [Electronic] United States
• PMID: 26719578 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Integrin alphaVbeta3
• Peptides, Cyclic

Topics

• Animals
• Cell Line, Tumor
• Combinatorial Chemistry Techniques
• Drug Delivery Systems (methods)
• Glioblastoma (metabolism)
• Humans
• Integrin alphaVbeta3 (metabolism)
• K562 Cells
• Mice
• Mice, Nude
• Molecular Structure
• Peptides, Cyclic (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship