Alpha v integrin affinity/specificity and antiangiogenesis effect of a novel tetraaza cyclic peptide derivative, SU015, in various species

The present study was undertaken to define the alpha v beta3 and alpha v beta5 binding potency and specificity of SU015, an integrin antagonist. SU015 inhibited alpha v beta3-mediated human umbilical vein endothelial cell or 293/beta3-transfected CHO cell adhesion to fibrinogen, with IC50 values of 0.21 +/- 0.11 muM and 0.32 +/- 0.02 microM. SU015 demonstrated comparable affinity to alpha v beta5 as compared with alpha v beta3 affinity, as well as a relatively high degree of specificity for human alpha v beta3- and alpha v beta5-mediated functions, as compared with other human integrins, including alphaIIbbeta3 (IC50 >100 microM), alpha5/beta1 (IC50 >100 microM), and alpha4/beta1 (IC50 >100 microM). SU015 demonstrated different degrees of species specificity in blocking alpha v beta3-mediated cellular adhesion, with relatively higher affinity to monkey (IC50 = 0.10 microM) and dog (IC50 = 1.30 microM) endothelial or smooth muscle cell alpha v beta3-mediated adhesion. Additionally, SU015 demonstrated a high degree of alpha v beta3 and alpha v beta5 specificity as compared with alpha4beta1-, alpha5beta1-, or alpha IIb beta3-mediated binding in the above species. In conclusion, SU015 is an alpha v beta3 and alpha v beta5 antagonist with relatively higher potency and specificity as compared with alpha IIb beta3, alpha5beta1, or alpha4beta1 integrins. Additionally, comparable alpha v beta3 and alpha v beta5 affinity for SU015 was demonstrated with human and monkey endothelial cells. These data also suggest that this bicyclic RGD analogue linked to a linker at the bottom leaves the RGD at the top available for binding and allows for conjugation with radioisotope for imaging and radiotherapy.