Computational analysis and determination of a highly conserved surface exposed segment in H5N1 avian flu and H1N1 swine flu neuraminidase

Ghosh, Ambarnil; Nandy, Ashesh; Nandy, Papiya
January 2010
BMC Structural Biology;2010, Vol. 10, p6
Academic Journal
Background: Catalytic activity of influenza neuraminidase (NA) facilitates elution of progeny virions from infected cells and prevents their self-aggregation mediated by the catalytic site located in the body region. Research on the active site of the molecule has led to development of effective inhibitors like oseltamivir, zanamivir etc, but the high rate of mutation and interspecies reassortment in viral sequences and the recent reports of oseltamivir resistant strains underlines the importance of determining additional target sites for developing future antiviral compounds. In a recent computational study of 173 H5N1 NA gene sequences we had identified a 50-base highly conserved region in 3'-terminal end of the NA gene. Results: We extend the graphical and numerical analyses to a larger number of H5N1 NA sequences (514) and H1N1 swine flu sequences (425) accessed from GenBank. We use a 2D graphical representation model for the gene sequences and a Graphical Sliding Window Method (GSWM) for protein sequences scanning the sequences as a block of 16 amino acids at a time. Using a protein sequence descriptor defined in our model, the protein sliding scan method allowed us to compare the different strains for block level variability, which showed significant statistical correlation to average solvent accessibility of the residue blocks; single amino acid position variability results in no correlation, indicating the impact of stretch variability in chemical environment. Close to the Cterminal end the GSWM showed less descriptor-variability with increased average solvent accessibility (ASA) that is also supported by conserved predicted secondary structure of 3' terminal RNA and visual evidence from 3D crystallographic structure. Conclusion: The identified terminal segment, strongly conserved in both RNA and protein sequences, is especially significant as it is surface exposed and structural chemistry reveals the probable role of this stretch in tetrameric stabilization. It could also participate in other biological processes associated with conserved surface residues. A RNA double hairpin secondary structure found in this segment in a majority of the H5N1 strains also supports this observation. In this paper we propose this conserved region as a probable site for designing inhibitors for broadspectrum pandemic control of flu viruses with similar NA structure.


Related Articles

  • Management of Influenza: Use of New Antivirals and Resistance in Perspective. Jackson, H.C.; Roberts, N.; Wang, Z.M.; Belshe, R. // Clinical Drug Investigation;2000, Vol. 20 Issue 6, p447 

    In most years epidemics of influenza cause a significant increase in morbidity and mortality worldwide. With the availability of a new class of antivirals targeting the viral protein neuraminidase, there are new options for the control of influenza. The use of the older antiviral agents (M2...

  • INFLUENZA VIRUS SURVEILLANCE BY THE INSTITUTO ADOLFO LUTZ, INFLUENZA SEASON 2014: ANTIVIRAL RESISTANCE. de Oliveira SANTOS, Katia Corrêa; da SILVA, Daniela Bernardes Borges; BENEGA, Margarete Aparecida; de Sousa PAULINO, Renato; SILVA Jr, Elian Reis E.; dos Santos PEREIRA, Dejanira; MUSSI, Aparecida Duarte Hg; da SILVA, Valéria Cristina; GUBAREVA, Larissa V.; de PAIVA, Terezinha Maria // Revista do Instituto de Medicina Tropical de Sao Paulo;Jan/Feb2015, Vol. 57 Issue 1, p92 

    A letter to the editor is presented in response to the article discussing topics which include use of Neuraminidase (NA) inhibitors (NAIs) for antiviral therapy, treatment of seasonal influenza A and B infections, and monitoring of antiviral resistance to assist public health authorities.

  • Oseltamivir Resistance – Disabling Our Influenza Defenses. Moscona, Anne // New England Journal of Medicine;12/22/2005, Vol. 353 Issue 25, p2633 

    The article focuses on the author's views on antiviral drugs to guard against influenza infections. The author says that the availability of antiviral drugs like neuraminidase inhibitors provides defenses against pandemic and seasonal influenza. The potential for an influenza pandemic has...

  • Selection of predicted siRNA as potential antiviral therapeutic agent against influenza virus. Raza, Asif; Shareef, Hira; Salim, Hira; Khushal, Rashid; Bokhari, Habib // Bioinformation;2011, Vol. 6 Issue 9, p340 

    Influenza virus A (IVA) infection is responsible for recent death worldwide. Hence, there is a need to develop therapeutic agents against the virus. We describe the prediction of short interfering RNA (siRNA) as potential therapeutic molecules for the HA (Haemagglutinin) and NA (Neuraminidase)...

  • Monitoring of neuraminidase inhibitor resistance among clinical infl uenza virus isolates in Japan during the 2003-2006 infl uenza seasons.  // Weekly Epidemiological Record;4/27/2007, Vol. 82 Issue 17, p149 

    The article cites a study which investigates the monitoring of neuraminidase inhibitor resistance among clinical influenza virus isolates in Japan in 2003-2006. In estimating the frequency of antiviral resistance in community isolates, it undertook screening susceptibility to oseltavimir of...

  • Surveillance de la résistance aux inhibiteurs de la neuraminidase dans les isolements cliniques de virus grippal au Japon au cours des saisons 2003 à 2006.  // Weekly Epidemiological Record;4/27/2007, Vol. 82 Issue 17, p149 

    The article cites a study which investigates the monitoring of neuraminidase inhibitor resistance among clinical influenza virus isolates in Japan in 2003-2006. In estimating the frequency of antiviral resistance in community isolates, it undertook screening susceptibility to oseltavimir of...

  • Neuraminidase Inhibitors in Pediatric Patients. Noyola, Daniel E. // Pediatric Drugs;2003, Vol. 5 Issue 2, p125 

    Influenza is responsible for annual epidemics, and is associated with significant morbidity and mortality. The development and use of antiviral agents is one of the recent strategies used to control influenza. Zanamivir and oseltamivir are members of a new class of antiviral agents, the...

  • GPs warned not to rely on antivirals in flu pandemic.  // Pulse;1/26/2006, Vol. 66 Issue 4, p19 

    The article reports on a research published by "The Lancet" regarding the effectiveness of antiviral drugs against avian flu or pandemic influenza viruses. The researchers warned general practitioners not to rely on antivirals to control a flu pandemic. In addition, neuraminidase inhibitors...

  • Molecular Dynamics Simulations Suggest that Electrostatic Funnel Directs Binding of Tamiflu to Influenza N1 Neuraminidases. Ly Le; Lee, Eric H.; Hardy, David J.; Truong, Thanh N.; Schulten, Klaus // PLoS Computational Biology;Sep2010, Vol. 6 Issue 9, p1 

    Oseltamivir (Tamiflu) is currently the frontline antiviral drug employed to fight the flu virus in infected individuals by inhibiting neuraminidase, a flu protein responsible for the release of newly synthesized virions. However, oseltamivir resistance has become a critical problem due to rapid...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics