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Novel Pure αVβ3 Integrin Antagonists That Do Not Induce Receptor Extension, Prime the Receptor, or Enhance Angiogenesis at Low Concentrations
ACS Pharmacology & Translational Science Pub Date : 2019-08-16 , DOI: 10.1021/acsptsci.9b00041
Jihong Li, Yoshiyuki Fukase, Yi Shang, Wei Zou, José M. Muñoz-Félix, Lorena Buitrago, Johannes van Agthoven, Yixiao Zhang, Ryoma Hara, Yuta Tanaka, Rei Okamoto, Takeshi Yasui, Takashi Nakahata, Toshihiro Imaeda, Kazuyoshi Aso, Yuchen Zhou, Charles Locuson, Dragana Nesic, Mark Duggan, Junichi Takagi, Roger D. Vaughan, Thomas Walz, Kairbaan Hodivala-Dilke, Steven L. Teitelbaum, M. Amin Arnaout, Marta Filizola, Michael A. Foley, Barry S. Coller

The integrin αVβ3 receptor has been implicated in several important diseases, but no antagonists are approved for human therapy. One possible limitation of current small-molecule antagonists is their ability to induce a major conformational change in the receptor that induces it to adopt a high-affinity ligand-binding state. In response, we used structural inferences from a pure peptide antagonist to design the small-molecule pure antagonists TDI-4161 and TDI-3761. Both compounds inhibit αVβ3-mediated cell adhesion to αVβ3 ligands, but do not induce the conformational change as judged by antibody binding, electron microscopy, X-ray crystallography, and receptor priming studies. Both compounds demonstrated the favorable property of inhibiting bone resorption in vitro, supporting potential value in treating osteoporosis. Neither, however, had the unfavorable property of the αVβ3 antagonist cilengitide of paradoxically enhancing aortic sprout angiogenesis at concentrations below its IC50, which correlates with cilengitide’s enhancement of tumor growth in vivo.
更新日期:2019-08-18

 

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