title: Targeting the ATP-dependent formation of herpesvirus ribonucleoprotein particle assembly as an antiviral approach.
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.
authors: School of Molecular and Cellular Biology, Leeds LS2 9JT, UK.|Astbury Centre for Structural Molecular Biology, Leeds LS2 9JT, UK.
authors: Sophie
authors: S
authors: Schumann
authors: School of Molecular and Cellular Biology, Leeds LS2 9JT, UK.|Astbury Centre for Structural Molecular Biology, Leeds LS2 9JT, UK.
authors: Brian R
authors: BR
authors: Jackson
authors: School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
authors: Ian
authors: I
authors: Yule
authors: School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
authors: Steven K
authors: SK
authors: Whitehead
authors: School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
authors: Charlotte
authors: C
authors: Revill
authors: Astbury Centre for Structural Molecular Biology, Leeds LS2 9JT, UK.|School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
authors: Richard
authors: R
authors: Foster
authors: School of Molecular and Cellular Biology, Leeds LS2 9JT, UK.|Astbury Centre for Structural Molecular Biology, Leeds LS2 9JT, UK.
authors: Adrian
authors: A
authors: Whitehouse
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000998:Antiviral Agents / Q000494:pharmacology*; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D057809:HEK293 Cells; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D012261:Ribonucleoproteins / Q000378:metabolism*; D019065:Virus Assembly
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D012261:Ribonucleoproteins; D000255:Adenosine Triphosphate; C487886:DDX39B protein, human; D053487:DEAD-box RNA Helicases