dc.contributor.authorWee, Keng Boon
dc.contributor.authorLee, Raphael Tze Chuen
dc.contributor.authorLin, Jing
dc.contributor.authorPramono, Zacharias Aloysius Dwi
dc.contributor.authorMaurer-Stroh, Sebastian
dc.contributor.editorKosakovsky Pond, Sergei L.*
dc.date.accessioned2016-02-19T07:15:36Z
dc.date.available2016-02-19T07:15:36Z
dc.date.issued2016
dc.identifier.citationWee, K. B., Lee, R. T. C., Lin, J., Pramono, Z. A. D., & Maurer-Stroh, S. (2016). Discovery of Influenza A Virus Sequence Pairs and Their Combinations for Simultaneous Heterosubtypic Targeting that Hedge against Antiviral Resistance. PLOS Computational Biology, 12(1), e1004663-.en_US
dc.identifier.issn1553-734Xen_US
dc.identifier.urihttp://hdl.handle.net/10220/40014
dc.description.abstractThe multiple circulating human influenza A virus subtypes coupled with the perpetual genomic mutations and segment reassortment events challenge the development of effective therapeutics. The capacity to drug most RNAs motivates the investigation on viral RNA targets. 123,060 segment sequences from 35,938 strains of the most prevalent subtypes also infecting humans–H1N1, 2009 pandemic H1N1, H3N2, H5N1 and H7N9, were used to identify 1,183 conserved RNA target sequences (≥15-mer) in the internal segments. 100% theoretical coverage in simultaneous heterosubtypic targeting is achieved by pairing specific sequences from the same segment (“Duals”) or from two segments (“Doubles”); 1,662 Duals and 28,463 Doubles identified. By combining specific Duals and/or Doubles to form a target graph wherein an edge connecting two vertices (target sequences) represents a Dual or Double, it is possible to hedge against antiviral resistance besides maintaining 100% heterosubtypic coverage. To evaluate the hedging potential, we define the hedge-factor as the minimum number of resistant target sequences that will render the graph to become resistant i.e. eliminate all the edges therein; a target sequence or a graph is considered resistant when it cannot achieve 100% heterosubtypic coverage. In an n-vertices graph (n ≥ 3), the hedge-factor is maximal (= n– 1) when it is a complete graph i.e. every distinct pair in a graph is either a Dual or Double. Computational analyses uncover an extensive number of complete graphs of different sizes. Monte Carlo simulations show that the mutation counts and time elapsed for a target graph to become resistant increase with the hedge-factor. Incidentally, target sequences which were reported to reduce virus titre in experiments are included in our target graphs. The identity of target sequence pairs for heterosubtypic targeting and their combinations for hedging antiviral resistance are useful toolkits to construct target graphs for different therapeutic objectives.en_US
dc.description.sponsorshipASTAR (Agency for Sci., Tech. and Research, S’pore)en_US
dc.format.extent24 p.en_US
dc.language.isoenen_US
dc.relation.ispartofseriesPLOS Computational Biologyen_US
dc.rights© 2016 Wee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.subjectBiological Sciences
dc.titleDiscovery of Influenza A Virus Sequence Pairs and Their Combinations for Simultaneous Heterosubtypic Targeting that Hedge against Antiviral Resistanceen_US
dc.typeJournal Article
dc.contributor.schoolSchool of Biological Sciencesen_US
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pcbi.1004663
dc.description.versionPublished versionen_US


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