Angiogenesis, the formation of new blood vessels, is crucial to a number of physiological processes such as reproduction, development and tissue repair, as well as in disease states including cancer, rheumatoid arthritis and other inflammatory diseases. Consequently angiogenesis represents an emerging therapeutic target which by 2006, is expected to command a market of $1.75 billion. Angiogenesis is a well-programmed cascade of events, which contains a number of distinct steps. One such step involves the migration and adhesion of endothelial cells to areas that are destined to become hyper-vascularized.

Adhesion to extracellular matrix through cell surface integrins facilitates cell proliferation, survival, and migration, and cytokine-stimulation of these processes. The complex integrin family of transmembrane proteins consists of heterodimers, each consisting of one alpha and one beta chain. VEGF potently induces microvascular ECs to express the alpha(1)beta(1) and alpha(2)beta(1) integrins and depending on cell type, these integrins generally bind collagens and laminins and both serve important functions in supporting VEGF signaling, EC migration, and tumor angiogenesis. Disintegrins represent a group of cysteine-rich peptides occurring in Crotalidae and Viperidae snake venoms, and are potent antagonists of several integrin receptors. A novel disintegrin, obtustatin, was isolated from the venom of the Vipera lebetina obtusa viper, and represents the first potent and selective inhibitor of the binding of integrin alpha(1)beta(1) to collagen IV. The primary structure of obtustatin contains 41 amino acids and is the shortest disintegrin described to date. Obtustatin shares the pattern of cysteines of other short disintegrins. However, in contrast to known short disintegrins, the integrin-binding loop of obtustatin is two residues shorter and does not express the classical RGD sequence. Using synthetic peptides, a KTS motif was identified as the integrin-binding sequence.


Although Obtustatin is a potent and selective inhibitor of alpha1beta1 integrin, it does not inhibit the closely related integrin alpha2beta1, or a panel of other integrins tested. Importantly, it has recently been reported that obtustatin potently inhibited angiogenesis in vivo in the chicken chorioallantoic membrane assay and in the Lewis lung syngeneic mouse model. Furthermore, Obtustatin also reduced tumor development by 50%, confirming and extending previous results on the relevance of alpha1beta1 integrin to angiogenesis and suggesting that this molecule may serve as a lead for the development of small molecule angiogenesis inhibitors.

Entry date Thursday, June 05, 2003

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