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Polymers carrying sLe x ‐mimetics are superior inhibitors of E‐selectin‐dependent leukocyte rolling in vivo
Author(s) -
Ali Majid,
Hicks Anne E.R.,
Hellewell Paul G.,
Thoma Gebhard,
Norman Keith E.
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-0346fje
Subject(s) - in vivo , selectin , intravital microscopy , chemistry , polylysine , cremaster muscle , in vitro , biophysics , pharmacology , conjugate , biochemistry , adhesion , medicine , biology , mathematical analysis , microbiology and biotechnology , mathematics , organic chemistry
Selectins mediate leukocyte rolling and may represent good anti‐inflammatory drug targets. Detailed knowledge regarding the structure of selectin ligands has permitted development of selectin antagonists with varying specificities and activity. Efficacy of monovalent selectin antagonists may be increased by presenting them on a polymer backbone. We have synthesized a range of multivalent selectin antagonists and characterized their activity by using intravital microscopy of the mouse cremaster muscle. The monovalent inhibitor CGP77175A inhibited E‐selectin‐dependent leukocyte rolling at a dose of 3 mg/kg. Multivalent presentation of CGP77175A on a modified polylysine backbone (degree of polymerization = 1200; 50% of the polylysines carry the inhibitor) greatly enhanced in vivo activity giving an inhibitor that produced an equivalent effect at 0.1 mg/kg. The polylysine conjugate was also longer acting than the monovalent antagonist. In spite of greatly enhanced activity against E‐selectin compared with monovalent inhibitor, the multivalent inhibitor had no measurable effect on P‐ or L‐selectin‐dependent leukocyte rolling.