Obtustatin: a potent selective inhibitor of alpha1beta1 integrin in vitro and angiogenesis in vivo.
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 alpha1beta1 integrin. It does not inhibit the closely related integrin alpha2beta1, nor a panel of other integrins tested. It does not inhibit ligand binding to the recombinant alpha1 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 alpha1beta1 integrin to angiogenesis and suggesting novel approaches to the generation of angiogenesis inhibitors.
Temple University, School of Medicine, Thrombosis Research Center, Philadelphia, Pennsylvania 19140, USA. cmarcink@nimbus.temple.edu
Cezary
C
Marcinkiewicz
Paul H
PH
Weinreb
Juan J
JJ
Calvete
Dariusz G
DG
Kisiel
Shaker A
SA
Mousa
George P
GP
Tuszynski
Roy R
RR
Lobb
D000482:Allantois / Q000098:blood supply; D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy; D002448:Cell Adhesion / Q000187:drug effects; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply; D002851:Chromatography, High Pressure Liquid; D019483:Disintegrins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D039222:Integrin alpha1beta1 / Q000037:antagonists & inhibitors*; D020014:K562 Cells; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014757:Viper Venoms / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D019483:Disintegrins; D039222:Integrin alpha1beta1; D014757:Viper Venoms; C474313:obtustatin, Vipera lebetina obtusa