Obtustatin: a potent selective α1β1 inhibitor

2018-09-21

Introduction 

Obtustatin isolated from the venom of the Vipera lebetina obtusa viper is a highly potent integrin α1β1 inhibitor (IC50 = 0.8 nM for α1β1 binding to type IV collagen). And α1β1 is selective for α2β1, αIIbβ3, αvβ3, α4β1, α5β6, α9β1 and α4β7. Besides, it inhibits FGF2-stimulated angiogenesis in the chicken chorioallantoic model and displays antitumor efficacy in a synergistic mouse model of Lewis lung carcinoma.

Pharmacologic action

The primary structure of obtustatin contains 41 amino acids, which is the shortest disintegrin described to date. And obtustatin has the same pattern of cysteines compared with other short disintegrins. However, the integrin-binding loop of obtustatin is two residues shorter and does not express classical RGD sequence, in contrast to the known short disintegrins. The KTS motif was identified as an integrin-binding sequence using synthetic peptides. The obtustatin's three-dimensional model was built by homology-modeling structure calculations using different templates and alignments, strongly indicating that the novel KTS motif may reside at the tip of a flexible loop. The action mechanism of obtustatin is related to the blocking of microvascular endothelial cell proliferation and undergoing apoptosis in caspase-dependent manner.

Function

In the chicken chorioallantoic membrane assay, obtustatin inhibited angiogenesis in vivo, potently. Obtustatin could also block human melanoma growth in nude mice. Obtustatin inhibited the neovascularization ratio on the CAM embryo of quail, which was pathologically induced by the developing tumor. In nude mice, obtustatin blocked cancer growth of MV3 human melanoma, completely. Besides, obtustatin reduced tumor development by half in the Lewis lung syngeneic mouse model, which confirmed and extended previous results on the relevance of α1β1 integrin to angiogenesis.

Pharmacokinetics and metabolism

The maximal tolerance dose (MTD) of obtustatin for this specie was established before performing the mouse experiments. When the obtustatin was injected once, the dose of i.v in the tail vein of mice was increased to 20 mg / kg. The experiment results suggested that behavioral signs and measurement of the body weight did not reveal any toxic side effects during 10 days of observation. The paraffin sections of brain, kidney, liver, lung and spleen were prepared and stained with H&E, after this period of time. And the analysis of these sections indicated no effects at all concentrations below 7 mg/kg. Nevertheless, in 10 mg/kg and 20 mg/kg groups, the liver of the animals showed small areas of necrotic patches and inflammations. Besides, there were small areas of necrosis in the spleen of some animals in the 10 mg/kg group and there were significant necrotic patches in all animals in the 20 mg/kg group. In all groups, no effects were observed in the brain, lung and kidney. Thus, MTD was determined to be 7 mg/kg based on this data.

References:

1. Moreno‐Murciano, M. P., Monleón, D., Calvete, J. J., Celda, B., & Marcinkiewicz, C. (2003). Amino acid sequence and homology modeling of obtustatin, a novel non‐RGD‐containing short disintegrin isolated from the venom of Vipera lebetina obtusa. Protein science, 12(2), 366-371.

2. Marcinkiewicz, C., Weinreb, P. H., Calvete, J. J., Kisiel, D. G., Mousa, S. A., Tuszynski, G. P., & Lobb, R. R. (2003). Obtustatin: a potent selective inhibitor of α1β1 integrin in vitro and angiogenesis in vivo. Cancer Research, 63(9), 2020-2023.

3. Brown, M. C., Staniszewska, I., Del Valle, L., Tuszynski, G. P., & Marcinkiewicz, C. (2008). Angiostatic activity of obtustatin as α1β1 integrin inhibitor in experimental melanoma growth. International journal of cancer, 123(9), 2195-2203.

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