Design and synthesis of E-selectin antagonists

Selectin-mediated recruitment of leukocytes plays a crucial role in a numbe r of diseases and pathological situations, for example in inflammation, rep erfusion injury, rheumatoid arthritis and respiratory diseases. Substantial research efforts are directed toward development of carbohydrate-derived d rugs 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 Lewis(x) (sLe(x)). One approach is based on the preorganization of mimics in their bioactive conf ormation to reduce entropic costs. For the conformational analysis of mimic s, molecular modeling based tools were developed. They allow the rational d esign of selectin antagonists with simplified structures, but increased inh ibitory potency. Alternatively, additional carbohydrate/lectin contacts can be identified for the improvement of enthalpic contributions. Following th is approach, an additional hydrophobic interaction of the antagonists with E-selectin leads to a 60-fold improvement of E-selectin affinity. Antagonis ts have been synthesized using chemical or chemoenzymatic methods. Finally, a flow chart for the biological evaluation of the antagonists is presented .