An emerging paradigm is that fragments of plasma or extracellular proteins may regulate angiogenesis. A known plasma protein has recently been identified as having anti-angiogenic activity only after proteolytic activation. This protein has no homology to previously identified proteins with anti-angiogenic activity e.g. angiostatin, thrombospondin. The specific binding of this activated protein to endothelial cells has been demonstrated. This results in the inhibition of endothelial cell proliferation in vitro (IC50 = 10 nM) as well as angiogenesis in vivo in a Matrigel Plug model. The migration of endothelial cells is also inhibited by this activated protein with an IC50 = 100 nM. Peptides based on the sequence of this protein have been synthesized and tested and l6-mer peptides with anti- proliferative activity against endothelial cells have been identified. The goal of this Phase I proposal is to identify the minimal sequences required for the inhibition of endothelial cell proliferation and migration and to optimize these peptides from the standpoint of activity and stability. Structure-based drug design will be used in Phase II to develop peptidomimetics based on the optimized peptide sequences. The goal of Phase II will be to identify a drug candidate peptide or peptidomimetic based on the sequence(s) of the optimized peptides identified in Phase I.
Pathological angiogenesis has been implicated in several major human disease states including cancer, arthritis, atherosclerosis and retinopathy. We propose to create a drug candidate which would specifically inhibit the proliferation of endothelial cells and could be usefii1 clinically as an anti- angiogenic agent. The therapeutic targeting of angiogenesis has been validated in vivo and may have application in both the acute and chronic use setting.
