Endogenous angiogenesis inhibitors
Director:
Aleksander S. Popel, Ph.D.
Brief Discription and findings:
We have designed bioinformatics algorithms to identify a set of putative angiogenesis inhibitors that are fragments of endogenous extracellular matrix or circulating proteins. The algorithms identified approximately 200 similarity hits for the proteins or protein fragments with known anti-angiogenic activity. Of the 200 hits, approximately 100 are distinct novel putative anti-angiogenic peptides. These peptides were derived from several protein families which include type IV collagen, CXC chemokines, and type I thrombospondin repeats containing proteins. To test our bioinformatic predictions, we performed in vitro studies using endothelial cell proliferation and migration assays. We have tested over 60 peptides and all of them exhibit anti-angiogenic properties, but the pattern of inhibition and dose response are different for different peptides. We have shown that these endogenous peptides suppress the proliferation and migration of HUVECs in vitro. By performing clustering analyses of the sequences using sequence similarity criteria and of the experimental results using a hierarchical algorithm, we reported that the clusters identified by the experimental results coincide with the sequence-based clusters, indicating a tight relationship between peptide sequence and anti-angiogenic potency. Pilot imaging experiments in mice with subcutaneous implantation of basement-membrane-extract plugs premixed with peptides also demonstrated their anti-angiogenic activity showing inhibition of neovascular invasion into the plugs. Experimental identification of several novel endogenous anti-angiogenic peptides would be an important step toward developing therapeutic agents for cancer treatment and other diseases associated with neovascularization.
Main publications: Karagiannis, E.D. and Popel, A.S., Anti-angiogenic peptides identified in thrombospondin type I domains. Biochem Biophys Res Commun, 2007. 359(1): p. 63-9.
Karagiannis, E.D. and Popel, A.S., Identification of novel short peptides derived from the alpha 4, alpha 5, and alpha 6 fibrils of type IV collagen with anti-angiogenic properties. Biochem Biophys Res Commun, 2007. 354(2): p. 434-9. |
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