We demonstrated that the mechanism of action of several different sialidases is essentially common and involves both the covalent intermediate (as with other retaining glycosidases) and the oxacarbenium. Both species are accessible within the enzyme active site under normal physiological conditions, but probably the rate-determining transition state is that for general base-catalysed nucleophilic substitution leading to the covalent intermediate. Since the two species differ significantly in their charge distribution, this result may have an important bearing upon the design of new and better inhibitors as transition-state analogues; whereas Relenza and Tamiflu both used DANA as their template, it might be fruitful to design mimics for the transition state of the actual rate-determining step.