| 1. |
- Orozovic, Goran, 1965-, et al.
(författare)
-
Detection of Resistance Mutations to Antivirals Oseltamivir and Zanamivir in Avian Influenza A Viruses Isolated from Wild Birds
- 2011
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:1
-
Tidskriftsartikel (refereegranskat)abstract
- The neuraminidase (NA) inhibitors oseltamivir and zanamivir are the first-line of defense against potentially fatal variants of influenza A pandemic strains. However, if resistant virus strains start to arise easily or at a high frequency, a new anti-influenza strategy will be necessary. This study aimed to investigate if and to what extent NA inhibitor–resistant mutants exist in the wild population of influenza A viruses that inhabit wild birds. NA sequences of all NA subtypes available from 5490 avian, 379 swine and 122 environmental isolates were extracted from NCBI databases. In addition, a dataset containing 230 virus isolates from mallard collected at Ottenby Bird Observatory (Öland, Sweden) was analyzed. Isolated NA RNA fragments from Ottenby were transformed to cDNA by RT-PCR, which was followed by sequencing. The analysis of genotypic profiles for NAs from both data sets in regard to antiviral resistance mutations was performed using bioinformatics tools. All 6221 sequences were scanned for oseltamivir- (I117V, E119V, D198N, I222V, H274Y, R292K, N294S and I314V) and zanamivir-related mutations (V116A, R118K, E119G/A/D, Q136K, D151E, R152K, R224K, E276D, R292K and R371K). Of the sequences from the avian NCBI dataset, 132 (2.4%) carried at least one, or in two cases even two and three, NA inhibitor resistance mutations. Swine and environmental isolates from the same data set had 18 (4.75%) and one (0.82%) mutant, respectively, with at least one mutation. The Ottenby sequences carried at least one mutation in 15 cases (6.52%). Therefore, resistant strains were more frequently found in Ottenby samples than in NCBI data sets. However, it is still uncertain if these mutations are the result of natural variations in the viruses or if they are induced by the selective pressure of xenobiotics (e.g., oseltamivir, zanamivir).
|
|
| 2. |
- Nicholls, Ian A., et al.
(författare)
-
Synthetic Neuraminidases : Nanostructured Materials for Environmental Monitoring
- 2011
-
Ingår i: Ecohealth, vol. 7, Supplement 1. - : Springer. ; , s. S97-S97
-
Konferensbidrag (refereegranskat)abstract
- The risks to society associated with the spread of new strains of influenza with human pathogenicity, or with impact on agricultureare significant. Our capacity to challenge the threat of the virus is dependent upon our ability to develop new vaccines, and upon ouraccess to effective virus-targeted small molecule pharmaceuticals. The current primary small molecule weapons oseltamivir(Tamiflu) and zanamivir (Relenza) currently form our last line of defence against this virus. More recently, the identification ofstrains resistant to (in particular) drugs targeting neuraminidase has awoken serious concern. Equally as worrying is the clearevidence of the presence of these substances in the World’s water systems which has now come forth. Collectively, this makes thedevelopment of techniques giving us better insight into the virus and antiviral agents a priority. Robust methods for the rapid andsensitive determination of these substances are required, especially as the monitoring methods should be able to withstand therigours of environments not normally conducive to biomacromolecules (temperature, toxic substances etc) e.g. antibodies.Advanced materials fulfilling these requirements can be obtained by Molecular Imprinting, which is a technique forproducing highly selective synthetic receptors for biochemical and chemical structures in synthetic polymers. The polymerscontain nano-structured cavities that are of complementary functional and structural character to predetermined target.The technique entails the judicious selection of a monomer or monomer mixture with chemical functionality comple-mentary to that of the imprint species (template). The complementary interacting functionalities (reversible covalent ornon-covalent) form predictable solution structures, which after polymerisation in the presence of a suitable cross linkingagent and removal of the template lead to the defining of recognition sites of complementary steric and functionaltopography to the template molecule. These sites give selective recognition of the template. Furthermore, by analogy tocatalytic antibody production, using transition state analogues as templates yields synthetic enzymes.Synthetic polymers with neuraminidase-like behaviour have been designed through the screening of candidate polymersystems using a combination of molecular dynamics and NMR studies. The characterisation of the resulting materials hasdemonstrated systems with selectivity for the targeted antiviral agents. Our studies illustrate the potential of these uniquenanostructured materials for the monitoring of these antiviral agents in the environment, which is an important aspect inefforts aimed at limiting the development of resistant strains, and as a tool for policy makers.
|
|
