Efomycine M, a new specific inhibitor of selectin, impairs leukocyte adhesion and alleviates cutaneous inflammation.
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.
Schön
Michael P
MP
Department of Dermatology, Otto-von-Guericke-University, Magdeburg, Germany. michael.schoen@medizin.uni-magdeburg.de
Krahn
Thomas
T
Schön
Margarete
M
Rodriguez
Maria-L
ML
Antonicek
Horst
H
Schultz
Jeanette E
JE
Ludwig
Ralf J
RJ
Zollner
Thomas M
TM
Bischoff
Erwin
E
Bremm
Klaus-D
KD
Schramm
Matthias
M
Henninger
Kerstin
K
Kaufmann
Roland
R
Gollnick
Harald P M
HP
Parker
Christina M
CM
Boehncke
W-Henning
WH
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D019040:E-Selectin / Q000187:drug effects*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects*; D018942:Macrolides / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008958:Models, Molecular; D009844:Oligosaccharides / Q000737:chemistry; D011565:Psoriasis / Q000188:drug therapy* / Q000473:pathology; D000080506:Sialyl Lewis X Antigen; D016038:Skin Transplantation; D013302:Streptomyces / Q000737:chemistry; D014183:Transplantation, Heterologous
D000894:Anti-Inflammatory Agents, Non-Steroidal; D019040:E-Selectin; D018942:Macrolides; D009844:Oligosaccharides; D000080506:Sialyl Lewis X Antigen; C453219:efomycine M