Design and Synthesis of E-Selectin Antagonists


  • Beat Ernst Institute of Molecular Pharmacy, Pharmacenter, University of Basel, Klingelbergstrasse 50, CH-4056 Basel
  • Zorica Dragic
  • Sébastien Marti
  • Christian Müller
  • Beatrice Wagner
  • Wolfgang Jahnke
  • John L. Magnani
  • Keith E. Norman
  • Reinhold Oehrlein
  • Thomas Peters
  • Hartmuth C. Kolb



Bioactive conformation, Chemical and chemo-enzymatic synthesis of glycomimetics, Molecular modeling, Preorganization, Selectin antagonists, Sialyl lewis x


Selectin-mediated recruitment of leukocytes plays a crucial role in a number of diseases and pathological situations, for example in inflammation, reperfusion injury, rheumatoid arthritis and respiratory diseases. Substantial research efforts are directed toward development of carbohydrate-derived drugs that interfere with the inflammatory response by blocking the selectin binding site. This article describes two approaches for the improvement of the inhibitory potency of the lead structure sialyl Lewisx (sLex). One approach is based on the preorganization of mimics in their bioactive conformation to reduce entropic costs. For the conformational analysis of mimics, molecular modeling based tools were developed. They allow the rational design of selectin antagonists with simplified structures, but increased inhibitory potency. Alternatively, additional carbohydrate/lectin contacts can be identified for the improvement of enthalpic contributions. Following this approach, an additional hydrophobic interaction of the antagonists with E-selectin leads to a 60-fold improvement of E-selectin affinity. Antagonists have been synthesized using chemical or chemoenzymatic methods. Finally, a flow chart for the biological evaluation of the antagonists is presented.




How to Cite

B. Ernst, Z. Dragic, S. Marti, C. Müller, B. Wagner, W. Jahnke, J. L. Magnani, K. E. Norman, R. Oehrlein, T. Peters, H. C. Kolb, Chimia 2001, 55, 268, DOI: 10.2533/chimia.2001.268.