Selectin inhibitors and their proposed role in ischemia and reperfusion

The selectin family of cellular adhesion molecules plays an important role in the cellular infiltration and molecular signaling associated with ischemia/reperfusion (I/R). Selectins are essential in the recruitment and infiltration of leukocytes to sites of inflammation, and consequently, selectin blockade represents an important area of current research in the potential alleviation of the cell-mediated injury associated with I/R. Previously, treatments targeted at only a single selectin have proven ineffective, due to compensation by uninhibited cell-adhesion molecules. However, pan-selectin antagonists-those inhibitors capable of blocking the actions of all three selectins-have demonstrated great potential in blocking the initial events in the leukocyte-endothelium adhesion cascade. A number of therapeutics have been developed, with the most promising results demonstrated by a class of non-oligosaccharide, small-molecule selectin antagonists. TB-1269 and OC-229 are two of the most promising of inhibitors in this class-they are capable of binding all three selectins, they have been demonstrated to reduce neutrophil infiltration following ischemia/reperfusion, and they have been associated with reduced tissue damage in experimental animal models of ischemia/reperfusion involving the liver, the heart, the kidneys, and the whole body. Furthermore, TBC-1269 has recently undergone successful phase I and phase IIa clinical trials for asthma and psoriasis. Though the timing of selectin inhibition is essential in attenuating leukocyte infiltration and cell-mediated injury, the transient blockade of selectin function, in a well-controlled setting, could be an extremely beneficial intervention in ischemia/reperfusion injury.