Development of withaferin A analogs as probes of angiogenesis |
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Authors: | Yokota Yasuno Bargagna-Mohan Paola Ravindranath Padma P Kim Kyung B Mohan Royce |
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Affiliation: | Department of Ophthalmology and Visual Science, University of Kentucky, Lexington, KY 40536, USA. |
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Abstract: | The natural product withaferin A (WFA) is a potent angiogenesis inhibitor and it targets the ubiquitin-proteasome pathway in vascular endothelial cells. We generated a biotinylated affinity analog WFA-LC(2)B for use as a probe to study angiogenesis. WFA-LC(2)B inhibits angiogenic sprouting in vitro and it causes levels of ubiquitinated proteins to increase in tumor necrosis factor-alpha-treated human umbilical vein endothelial cells, confirming the retention of WFA's biological activity. We show that WFA-LC(2)B forms protein adducts in endothelial cells which are competed by free WFA in vivo. This WFA-LC(2)B analog will be useful to isolate the biological target of WFA. |
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