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Targeting the ATP-dependent formation of herpesvirus ribonucleoprotein particle assembly as an antiviral approach

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Abstract

Human herpesviruses are responsible for a range of debilitating acute and recurrent diseases, including a number of malignancies. Current treatments are limited to targeting the herpesvirus DNA polymerases, but with emerging viral resistance and little efficacy against the oncogenic herpesviruses, there is an urgent need for new antiviral strategies. Here, we describe a mechanism to inhibit the replication of the oncogenic herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV), by targeting the ATP-dependent formation of viral ribonucleoprotein particles (vRNPs). We demonstrate that small-molecule inhibitors which selectively inhibit the ATPase activity of the cellular human transcription/export complex (hTREX) protein UAP56 result in effective inhibition of vRNP formation, viral lytic replication and infectious virion production. Strikingly, as all human herpesviruses use conserved mRNA processing pathways involving hTREX components, we demonstrate the feasibility of this approach for pan-herpesvirus inhibition.

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Figure 1: ATP-cycle-dependent remodelling of hTREX affects ORF57-mediated vRNP formation.
Figure 2: Identification of UAP56-targeted ATPase inhibitor.
Figure 3: CCT018159 disrupts formation and function of the vRNP, but not of the endogenous hTREX complex.
Figure 4: Disruption of virus lytic replication and infectious virion production by CCT018159.
Figure 5: Inhibition of α- and β-herpesvirus replication by CCT018159.

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  • 14 July 2017

    In the PDF version of this article previously published, the year of publication provided in the footer of each page and in the 'How to cite' section was erroneously given as 2017, it should have been 2016. This error has now been corrected. The HTML version of the article was not affected.

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Acknowledgements

The authors thank J. Jung (UCLA), S. Efstathiou and J. Sinclair (Cambridge) for cell lines and recombinant viruses, and S. Wilson (Sheffield), R. Reed (Harvard), T. Stamminger (Erlangen) and R.M. Sandri-Goldin (Irvine) for the gift of antibodies and plasmid constructs. The authors also thank I. Mainfield, Centre for Biomolecular Interactions, Faculty of Biological Sciences, for advice. This work was supported in part by the Wellcome Trust (093788/Z/10/Z); Worldwide Cancer Research (12-1045), BBSRC (BB/000306; BB/M006557) and CRUK (C12057/A19430).

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S.S. designed and performed experiments, analysed data and wrote the manuscript. B.R.J. performed experiments and analysed data. I.Y. performed the virtual high-throughput screening and modelling. S.K.W. and C.R. synthesized tested compounds. R.F. and A.W. designed and performed experiments, analysed data and wrote the manuscript.

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Correspondence to Richard Foster or Adrian Whitehouse.

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The authors declare no competing financial interests.

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Schumann, S., Jackson, B., Yule, I. et al. Targeting the ATP-dependent formation of herpesvirus ribonucleoprotein particle assembly as an antiviral approach. Nat Microbiol 2, 16201 (2017). https://doi.org/10.1038/nmicrobiol.2016.201

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