Abstract
Specific interference with molecular mechanisms guiding tissue localization of leukocytes may be of great utility for selective immunosuppressive therapies. We have discovered and characterized efomycines, a new family of selective small-molecule inhibitors of selectin functions. Members of this family significantly inhibited leukocyte adhesion in vitro. Efomycine M, which was nontoxic and showed the most selective inhibitory effects on selectin-mediated leukocyte-endothelial adhesion in vitro, significantly diminished rolling in mouse ear venules in vivo as seen by intravital microscopy. In addition, efomycine M alleviated cutaneous inflammation in two complementary mouse models of psoriasis, one of the most common chronic inflammatory skin disorders. Molecular modeling demonstrated a spatial conformation of efomycines mimicking naturally occurring selectin ligands. Efomycine M might be efficacious in the treatment of human inflammatory disorders through a similar mechanism.
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Acknowledgements
We thank R. Kubitza, J. Herz, and K. Hardt-Weinelt for technical assistance; I. Kruse, I. Hagelschuer and M. Kock for help with animal care; O. Gutbrod and D. Gondol for help with analysis of three-dimensional molecular structures; M. Kazinski for help with cell sorting; and T. Henkel and K. Weber for compound synthesis.
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T.K. has taken over a patent on the use of efomycines. However, there is no financial gain or benefit foreseeable and no financial profit has been made.
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Schön, M., Krahn, T., Schön, M. et al. Efomycine M, a new specific inhibitor of selectin, impairs leukocyte adhesion and alleviates cutaneous inflammation. Nat Med 8, 366–372 (2002). https://doi.org/10.1038/nm0402-366
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DOI: https://doi.org/10.1038/nm0402-366
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