Scientists have identified a fully functional small-molecule mimic of superoxide dismutase (SOD) that is ~60-fold smaller than the native enzyme (Science 286, 304–306, 1999). When injected intravenously into rats, the mimic prevents inflammatory damage or ischemic injury resulting from superoxide anions. According to Daniela Salvemini and Dennis Riley, senior authors on the paper, a painstaking search of over 100 molecules culminated in the identification of M40403, a molecule with catalytic activity/substrate specificity comparable to the natural enzyme. The authors first chose manganese as the reactive center due to its low toxicity, and then turned to computer modeling and structure–activity relationship analysis to find the surrounding molecular structure. When M40403 was tested in a rat footpad model of inflammation, it prevented both neutrophil infiltration and the production of inflammatory cytokines. Potent antiinflammatory and cytoprotective activities were also demonstrated in a rat model of ischemia-perfusion injury and shock, the mimic significantly prolonging survival time. "We now have a real pharmacological tool to explore the selective role of superoxide in health and disease," says Salvemini. While the current mimics must be injected, orally available versions are also planned by MetaPhore Pharmaceuticals (St Louis, MO).