Issue Date: February 23, 2009
Ligand Redesign Could Boost Nerve Repair
In research with implications for nerve-damage repair, a carbohydrate ligand of a protein associated with axon regeneration in neurons has been redesigned to create more potent analogs. The achievement is unusual, as carbohydrates have only rarely been transformed into mimics with greatly improved activity, notes Beat Ernst of the University of Basel, in Switzerland, who led the study (J. Med. Chem., DOI: 10.1021/jm801058n). A tetrasaccharide portion of the ganglioside GQ1bα is a ligand of myelin-associated glycoprotein (MAG), which is believed to control nerve growth. But the ligand's binding affinity is weak, and MAG's shallow binding site prevents the ligand from staying bound for long. Ernst and coworkers studied the interaction via saturation transfer difference NMR spectroscopy and used the analysis to redesign the tetrasaccharide. One structural change involved replacing one of the tetrasaccharide's hydrophilic neuraminic acid groups with a hydrophobic biphenyl substituent (shown). The best analogs have nearly 400-fold improved binding affinity, stemming mainly from the enhanced half-life of the MAG-ligand complex—a property favorable to potential use as drug leads. The work should aid validation of MAG's role in axon regeneration.
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