Inhibition of viral group-1 and group-2 neuraminidases by oseltamivir: A comparative structural analysis by the ScrewFit algorithm |
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| Authors: | Paolo A Calligari Gerald R Kneller Andrea Giansanti Paolo Ascenzi Alessandro Porrello Alessio Bocedi |
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| Institution: | 1. Centre de Biophysique Moléculaire, CNRS UPR 4301, Rue Charles Sadron, F-45071 Orléans Cedex 2, France;2. Institut Laue-Langevin, 6 Rue Jules Horowitz BP 156, F-38042 Grenoble Cedex, France;3. Laboratoire Léon Brillouin, CNRS UMR 12, F-91191 Gif-sur-Yvette, France;4. Université d''Orléans, Château de la Source — Avenue du Parc Floral, F-45067 Orléans, France;5. Synchroton SOLEIL, Saint Aubin BP48, F-91192 Gif-sur-Yvette Cedex, France;6. Dipartimento di Fisica, Università Roma La Sapienza, Piazzale Aldo Moro 5, I-00185 Roma, Italy;g Istituto Nazionale per le Malattie Infettive IRCCS ‘Lazzaro Spallanzani’, Via Portuense 292, I-00149 Roma, Italy;h Laboratorio Interdipartimentale di Microscopia Elettronica, Università Roma Tre, Via della Vasca Navale 79, I-00146 Roma, Italy;i Institute for Genome Sciences and Policy, Duke University, 101 Science Drive, Durham, NC 27708, USA |
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| Abstract: | 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. |
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| Keywords: | flu influenza H hemagglutinin NA neuraminidase |
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