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Obtustatin

A Potent Selective Inhibitor of 1ß1 Integrin in Vitro and Angiogenesis in Vivo¹

Temple University, School of Medicine, Thrombosis Research Center, Philadelphia, Pennsylvania 19140 [C. M., D. G. K., G. P. T.]; Biogen, Inc., Cambridge, Massachusetts 02142 [P. H. W., R. R. L.]; Instituto de Biomedicina, C.S.I.C., 46010 Valencia, Spain [J. J. C.]; and Albany College of Pharmacy and PRI at Albany, Albany, New York 12208 [S. A. M.]

A novel disintegrin, obtustatin, was purified from the venom of the Vipera lebetina obtusa viper. Obtustatin is the shortest disintegrin yet described, containing only 41 amino acids. It contains a similar pattern of cysteines to the short disintegrins echistatin and eristostatin but contains the sequence KTS rather than RGD in its active site loop. Obtustatin is a potent and selective inhibitor of 1ß1 integrin. It does not inhibit the closely related integrin 2ß1, nor a panel of other integrins tested. It does not inhibit ligand binding to the recombinant 1 I-domain. Importantly, obtustatin potently inhibited angiogenesis in vivo in the chicken chorioallantoic membrane assay, and in the Lewis lung syngeneic mouse model, it reduced tumor development by half, confirming and extending previous results on the relevance of 1ß1 integrin to angiogenesis and suggesting novel approaches to the generation of angiogenesis inhibitors.

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