Structural Biology Research Center, PF-IMSS-KEK^* Griffith University^** CSIRO^*** WEHI^**** University of Milano-Bicocca^***** University of Milano^****** University of Brescia^*******
○Leonard M G Chavas^* Ryuichi Kato^* Maretta C. Mann^** Robin J. Thomson^** Jeffrey C. Dyason^** Marc von Itzstein^** Jennifer McKimm-Breschkin^*** Peter M. Colman^**** Paola Fusi^***** Bruno Venerando^***** Guido Tettamanti^****** Eugenio Monti^******* Soichi Wakatsuki^*

Neuraminidases, or sialidases, are glycohydrolytic enzymes widely distributed among species. They catalyze the removal of sialic acid on the non-reducing termini of complex carbohydrates, and act in infection processes, signal transduction, intercellular interactions, glycoconjugate degradation etc. The infectivity of some viruses such as influenza virus is dependent on sialidase’s function. Therefore, the influenza virus neuraminidase (NA) is the target of drug designs for clinical treatment of the infection. Within species, sialidases diverge in their amino acid sequences, but assume a similar folding by means of a six bladed beta-propeller, and share an almost identical active site architecture. Consequently, drugs targeted to one virus strain’s neuraminidase expectedly acts on other strains as well. Here we report the inhibition studies of the human sialidase Neu2 by NA inhibitors such as Tamiflu, Zanamivir or Peramivir, as indicated by inhibition assays and X-ray structure determinations. As a preliminary result, whereas Tamiflu is inactive against the cytosolic Neu2, Zanamivir and Peramivir considerably affect the human enzyme’s activity by entering its active site. These studies open an area of more specific drug developments based on the crystal structures of the complexes.