Novel Pure αVβ3 Integrin Antagonists That
Do Not Induce Receptor Extension, Prime the Receptor, or Enhance Angiogenesis
at Low Concentrations
Posted on 2019-08-16 - 16:04
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.
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Li, Jihong; Fukase, Yoshiyuki; Shang, Yi; Zou, Wei; Muñoz-Félix, José M.; Buitrago, Lorena; et al. (2019). Novel Pure αVβ3 Integrin Antagonists That
Do Not Induce Receptor Extension, Prime the Receptor, or Enhance Angiogenesis
at Low Concentrations. ACS Publications. Collection. https://doi.org/10.1021/acsptsci.9b00041