Development of withaferin A analogs as probes of angiogenesis

Yasuno Yokota; Paola Bargagna-Mohan; Padma P. Ravindranath; Kyung B. Kim; Royce Mohan

doi:10.1016/j.bmcl.2006.02.039

Development of withaferin A analogs as probes of angiogenesis

Yasuno Yokota, Paola Bargagna-Mohan, Padma P. Ravindranath, Kyung B. Kim, Royce Mohan

Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

57 Scopus citations

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-LC₂B for use as a probe to study angiogenesis. WFA-LC₂B inhibits angiogenic sprouting in vitro and it causes levels of ubiquitinated proteins to increase in tumor necrosis factor-α-treated human umbilical vein endothelial cells, confirming the retention of WFA's biological activity. We show that WFA-LC₂B forms protein adducts in endothelial cells which are competed by free WFA in vivo. This WFA-LC₂B analog will be useful to isolate the biological target of WFA.

Original language	English
Pages (from-to)	2603-2607
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	16
Issue number	10
DOIs	https://doi.org/10.1016/j.bmcl.2006.02.039
State	Published - May 15 2006

Bibliographical note

Funding Information:
This work was supported by Fight-for-Sight Foundation Grant-in-Aid, Kentucky Tobacco Research & Development Center, and NIH (NS053593) grants to R.M. and a Research to Prevent Blindness Challenge Grant.

Funding

This work was supported by Fight-for-Sight Foundation Grant-in-Aid, Kentucky Tobacco Research & Development Center, and NIH (NS053593) grants to R.M. and a Research to Prevent Blindness Challenge Grant.

Funders	Funder number
Fight for Sight Foundation
National Institutes of Health (NIH)	NS053593
National Institutes of Health (NIH)
National Eye Institute/National Institutes of Health	R01EY016782
National Eye Institute/National Institutes of Health
The Kentucky Tobacco Research and Development Center

Keywords

Angiogenesis inhibitor
Binding protein
Biotinylated analog
Natural product
Ubiquitin

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2006.02.039

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title = "Development of withaferin A analogs as probes of angiogenesis",

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-LC2B for use as a probe to study angiogenesis. WFA-LC2B inhibits angiogenic sprouting in vitro and it causes levels of ubiquitinated proteins to increase in tumor necrosis factor-α-treated human umbilical vein endothelial cells, confirming the retention of WFA's biological activity. We show that WFA-LC2B forms protein adducts in endothelial cells which are competed by free WFA in vivo. This WFA-LC2B analog will be useful to isolate the biological target of WFA.",

keywords = "Angiogenesis inhibitor, Binding protein, Biotinylated analog, Natural product, Ubiquitin",

author = "Yasuno Yokota and Paola Bargagna-Mohan and Ravindranath, \{Padma P.\} and Kim, \{Kyung B.\} and Royce Mohan",

note = "Funding Information: This work was supported by Fight-for-Sight Foundation Grant-in-Aid, Kentucky Tobacco Research \& Development Center, and NIH (NS053593) grants to R.M. and a Research to Prevent Blindness Challenge Grant. ",

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language = "English",

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AU - Yokota, Yasuno

AU - Bargagna-Mohan, Paola

AU - Ravindranath, Padma P.

AU - Kim, Kyung B.

AU - Mohan, Royce

N1 - Funding Information: This work was supported by Fight-for-Sight Foundation Grant-in-Aid, Kentucky Tobacco Research & Development Center, and NIH (NS053593) grants to R.M. and a Research to Prevent Blindness Challenge Grant.

PY - 2006/5/15

Y1 - 2006/5/15

N2 - 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-LC2B for use as a probe to study angiogenesis. WFA-LC2B inhibits angiogenic sprouting in vitro and it causes levels of ubiquitinated proteins to increase in tumor necrosis factor-α-treated human umbilical vein endothelial cells, confirming the retention of WFA's biological activity. We show that WFA-LC2B forms protein adducts in endothelial cells which are competed by free WFA in vivo. This WFA-LC2B analog will be useful to isolate the biological target of WFA.

AB - 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-LC2B for use as a probe to study angiogenesis. WFA-LC2B inhibits angiogenic sprouting in vitro and it causes levels of ubiquitinated proteins to increase in tumor necrosis factor-α-treated human umbilical vein endothelial cells, confirming the retention of WFA's biological activity. We show that WFA-LC2B forms protein adducts in endothelial cells which are competed by free WFA in vivo. This WFA-LC2B analog will be useful to isolate the biological target of WFA.

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KW - Binding protein

KW - Biotinylated analog

KW - Natural product

KW - Ubiquitin

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Development of withaferin A analogs as probes of angiogenesis

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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