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Efomycine M, a new specific inhibitor of selectin, impairs leukocyte adhesion and alleviates cutaneous inflammation

Nature Medicine volume 8, pages 366–372 (2002)Cite this article

An Erratum to this article was published on 01 June 2002

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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Figure 1: Efomycines inhibit selectin-mediated functions in vitro.
Figure 2
Figure 3: Efomycine M inhibits selectin-mediated leukocyte rolling in vivo.
Figure 4: Low in vitro toxicity and low in vivo plasma clearance of efomycine M.
Figure 5: Efomycine M effectively alleviates hyperproliferative inflammatory skin lesions in a T cell–mediated mouse model of psoriasis.
Figure 6: NMR-based molecular modeling shows similar three-dimensional structures of efomycine M and sialyl LewisX.

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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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Authors and Affiliations

  1. Department of Dermatology, Otto-von-Guericke-University, Magdeburg, Germany

    Michael P. Schön, Margarete Schön & Harald P. M. Gollnick

  2. Pharmaceutical Research, Bayer AG, Wuppertal, Germany

    Thomas Krahn, Erwin Bischoff, Klaus-D. Bremm, Matthias Schramm & Kerstin Henninger

  3. Central Research, Bayer AG, Leverkusen, Germany

    Maria-L. Rodriguez & Horst Antonicek

  4. Department of Dermatology, Johann-Wolfgang-Goethe University, Frankfurt, Germany

    Jeanette E. Schultz, Ralf J. Ludwig, Thomas M. Zollner, Roland Kaufmann & W.-Henning Boehncke

  5. Division of Rheumatology, Immunology, & Allergy, Brigham & Women's Hospital, Boston, USA

    Christina M. Parker

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Correspondence to Michael P. Schön or W.-Henning Boehncke.

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Competing interests

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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