We have discovered through structure-based drug design a novel, potent, selective, and orally active influenza neuraminidase inhibitor (8) that is structurally different from existing neuraminidase inhibitors. Protein crystallography was used to screen compounds containing mixtures of isomers in order to identify the active isomer. In vitro studies showed that the potency of 8 is either comparable or superior to that of zanamivir and GS4071, and it is highly specific for influenza neuraminidase with at least 4 orders of magnitude less inhibitory activity against bacterial and mammalian neuraminidases. Oral efficacy studies in a mouse influenza model demonstrated that compound 8 was efficacious at a dose as low as 0.1 mg/kg/day b.i.d., with 7/9 mice surviving in the treated infected group compared to only 1/9 in the untreated infected group. Due to its in vitro and in vivo activity against influenza A and B, further studies with 8 in humans are warranted, and it is currently in human clinical trials for the management of influenza.