The deregulation of angiogenesis is involved in cancer and inflammatory diseases. The development of molecules able to control angiogenesis is therefore the subject of intense research. Vascular endothelial growth factor A (VEGF) is the main pro-angiogenic factor. Peptides able to bind the VEGF and disrupt its interaction with the cellular receptors VEGFR1 and VEGFR2 have been identified by Genentech. In particular, the peptide v114* (VEPNCDIHVnLWEWECFERL-NH2, with the two cysteines involved in a disulfide bond) was chosen as a starting point for our SAR studies, because a potent Kiof 60 nM has recently been determined.A detailed SAR study of the peptide v114* will be presented, including the incorporation of non-natural amino-acids, the variation of the macrocycle ring size and the introduction of additional side chains covalent constraints for the stabilization of an a-helical segment. Biochemical activity evaluation was made by Elisa type displacement assays of the VEGFR1 / btVEGF interaction, completed by ITC measurements with (VEGF11-107)2, allowing the determination of thermodynamic parameters of binding. The efficiency of the strategy was further supported by X-ray diffraction analysis of (VEGF11-107)2co-crystallized with one of the constrained analogs (figure).These findings provide a strong basis for further optimization of VEGF binding peptidomimetics with increased rigidity and protease stability, decreased size, and overall better drug-like properties.

Structure activity relationship studies on a vascular endothelial growth factor binding peptide

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.