Inhibition of viral group-1 and group-2 neuraminidases by oseltamivir: A comparative structural analysis by the ScrewFit algorithm

Paolo A. Calligari (1) , Gerald R. Kneller (1) , Andrea Giansanti , Paolo Ascenzi , Alessandro Porrello , Alessio Bocedi

1 CBM - Centre de biophysique moléculaire

The viral surface glycoprotein neuraminidase (NA) allows the influenza virus penetration and the egress of virions. NAs are classified as A, B, and C. Type-A NAs from influenza virus are subdivided into two phylogenetically distinct families, group-1 and group-2. NA inhibition by oseltamivir represents a therapeutic approach against the avian influenza virus H5N1. Here, structural bases for oseltamivir recognition by group-1 NA1, NA8 and group-2 NA9 are highlighted by the ScrewFit algorithm for quantitative structure comparison. Oseltamivir binding to NA1 and NA8 affects the geometry of Glu119 and of regions Arg130-Ser160, Val240-Gly260, and Asp330-Glu382, leading to multiple NA conformations. Additionally, although NA1 and NA9 share almost the same oseltamivir-bound final conformation, they show some relevant differences as suggested by the ScrewFit algorithm. These results indicate that the design of new NA inhibitors should take into account these family-specific effects induced on the whole structure of NAs.

Mots clés: neuraminidase; NA; flu; ScrewFit algorithm; oseltamivir binding; enzyme structure; comparative structural analysis

Domaines: Biophysique [physics.bio-ph]

Paolo A. Calligari, Gerald R. Kneller, Andrea Giansanti, Paolo Ascenzi, Alessandro Porrello, et al.. Inhibition of viral group-1 and group-2 neuraminidases by oseltamivir: A comparative structural analysis by the ScrewFit algorithm. Biophysical Chemistry, 2009, 141 (1), pp.117. ⟨10.1016/j.bpc.2009.01.004⟩. ⟨hal-00531141⟩