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Influenza virus-host interactome screen as a platform for antiviral drug development.

ABSTRACT: Host factors required for viral replication are ideal drug targets because they are less likely than viral proteins to mutate under drug-mediated selective pressure. Although genome-wide screens have identified host proteins involved in influenza virus replication, limited mechanistic understanding of how these factors affect influenza has hindered potential drug development. We conducted a systematic analysis to identify and validate host factors that associate with influenza virus proteins and affect viral replication. After identifying over 1,000 host factors that coimmunoprecipitate with specific viral proteins, we generated a network of virus-host protein interactions based on the stage of the viral life cycle affected upon host factor downregulation. Using compounds that inhibit these host factors, we validated several proteins, notably Golgi-specific brefeldin A-resistant guanine nucleotide exchange factor 1 (GBF1) and JAK1, as potential antiviral drug targets. Thus, virus-host interactome screens are powerful strategies to identify targetable host factors and guide antiviral drug development.

SUBMITTER: Watanabe T

PROVIDER: S-EPMC4451456 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Influenza virus-host interactome screen as a platform for antiviral drug development.

Watanabe Tokiko T Kawakami Eiryo E Shoemaker Jason E JE Lopes Tiago J S TJ Matsuoka Yukiko Y Tomita Yuriko Y Kozuka-Hata Hiroko H Gorai Takeo T Kuwahara Tomoko T Takeda Eiji E Nagata Atsushi A Takano Ryo R Kiso Maki M Yamashita Makoto M Sakai-Tagawa Yuko Y Katsura Hiroaki H Nonaka Naoki N Fujii Hiroko H Fujii Ken K Sugita Yukihiko Y Noda Takeshi T Goto Hideo H Fukuyama Satoshi S Watanabe Shinji S Neumann Gabriele G Oyama Masaaki M Kitano Hiroaki H Kawaoka Yoshihiro Y

Cell host & microbe 20141120 6

Host factors required for viral replication are ideal drug targets because they are less likely than viral proteins to mutate under drug-mediated selective pressure. Although genome-wide screens have identified host proteins involved in influenza virus replication, limited mechanistic understanding of how these factors affect influenza has hindered potential drug development. We conducted a systematic analysis to identify and validate host factors that associate with influenza virus proteins and ...[more]

PMID: 25464832

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Project description:BackgroundHost factors of influenza virus replication are often found in key topological positions within protein-protein interaction networks. This work explores how protein states can be manipulated through controllability analysis: the determination of the minimum manipulation needed to drive the cell system to any desired state. Here, we complete a two-part controllability analysis of two protein networks: a host network representing the healthy cell state and an influenza A virus-host network representing the infected cell state. In this context, controllability analyses aim to identify key regulating host factors of the infected cell's progression. This knowledge can be utilized in further biological analysis to understand disease dynamics and isolate proteins for study as drug target candidates.ResultsBoth topological and controllability analyses provide evidence of wide-reaching network effects stemming from the addition of viral-host protein interactions. Virus interacting and driver host proteins are significant both topologically and in controllability, therefore playing important roles in cell behavior during infection. Functional analysis finds overlap of results with previous siRNA studies of host factors involved in influenza replication, NF-kB pathway and infection relevance, and roles as interferon regulating genes. 24 proteins are identified as holding regulatory roles specific to the infected cell by measures of topology, controllability, and functional role. These proteins are recommended for further study as potential antiviral drug targets.ConclusionsSeasonal outbreaks of influenza A virus are a major cause of illness and death around the world each year with a constant threat of pandemic infection. This research aims to increase the efficiency of antiviral drug target discovery using existing protein-protein interaction data and network analysis methods. These results are beneficial to future studies of influenza virus, both experimental and computational, and provide evidence that the combination of topology and controllability analyses may be valuable for future efforts in drug target discovery.

Dataset Information

Influenza virus-host interactome screen as a platform for antiviral drug development.

Publications

Influenza virus-host interactome screen as a platform for antiviral drug development.

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