Fragment-based drug discovery, combinatorial chemistry, and in situ click chemistry have been teamed together to rapidly identify a carbohydrate-like inhibitor for a key glycoprotein of unknown structure (Angew. Chem. Int. Ed. 2010, 49, 5721). The approach is potentially valuable because such glycomimetic inhibitors are rare and the structures of many glycoproteins are unavailable. Beat Ernst of the University of Basel, in Switzerland, and coworkers were seeking an inhibitor of myelin-associated glycoprotein (MAG) that might promote axonal regeneration after an injury, a process MAG normally blocks. The researchers started with a known sialic acid-based MAG ligand. Using NMR spectroscopy to screen a combinatorial library of druglike compounds, they identified a nitroindole that binds MAG while the sialic acid-based ligand is already bound. With MAG as a template to position the two ligand fragments optimally, they used in situ click chemistry to form a triazole link between the fragments. The resulting combination agent binds MAG with an affinity of 190 nM, better than that of any other MAG antagonist. The agent is currently under further biological investigation as a potential drug lead, the researchers note.