1 Influenza Virus Sialidase: A Target for Drug Discovery

Abstract

Publisher Summary Influenza has probably been in existence for much of the history of man. Influenza viruses are members of the orthomyxoviridae family which are further classified, on serological differences, into three distinct types, that is A, B, and C. The human population appears to be most affected by types A and B, with the elderly, the very young and those with existing conditions such as chronic pulmonary and heart disease being most susceptible. The influenza virus undergoes frequent and rapid mutations in its surface antigens. It is this characteristic of the virus which results in the limited efficacy of influenza vaccines and, until recently, has hindered the development of effective specific anti-influenza agents. Of more importance in terms of the fight against influenza is the fact that often the virus undergoes a major antigenic transformation, resulting in a pandemic strain of the virus. The determination of the crystal structure of influenza virus sialidase provided the basis of the information necessary to prepare the appropriate structural modification of Neu5Ac2en in an attempt to develop more potent inhibitors. With the data from the crystallographic studies, particularly those with inhibitors bound in the catalytic site, the von Itzstein group set about a rational drug design approach. The benefits of using a rational drug design strategy are exemplified in the development of zanamivir, a highly potent inhibitor of influenza virus sialidase. The success of structure-based drug design studies with influenza virus, drawing on the information derived from protein crystallographic studies, molecular modeling and computational chemistry analysis, an understanding of the enzyme mechanism, and synthetic chemistry, may provide encouragement for future efforts targeted at other disease states.