title: Broad and potent antiviral activity of the NAE inhibitor MLN4924.
abstract: In terms of infected human individuals, herpesviruses range among the most successful virus families. Subclinical herpesviral infections in healthy individuals contrast with life-threatening syndromes under immunocompromising and immunoimmature conditions. Based on our finding that cytomegaloviruses interact with Cullin Roc ubiquitin ligases (CRLs) in the context of interferon antagonism, we systematically assessed viral dependency on CRLs by utilizing the drug MLN4924. CRL activity is regulated through the conjugation of Cullins with the ubiquitin-like molecule Nedd8. By inhibiting the Nedd8-activating Enzyme (NAE), MLN4924 interferes with Nedd8 conjugation and CRL activity. MLN4924 exhibited pronounced antiviral activity against mouse and human cytomegalovirus, herpes simplex virus (HSV)- 1 (including multi-drug resistant clinical isolates), HSV-2, adeno and influenza viruses. Human cytomegalovirus genome amplification was blocked at nanomolar MLN4924 concentrations. Global proteome analyses revealed that MLN4924 blocks cytomegaloviral replication despite increased IE1 amounts. Expression of dominant negative Cullins assigned this IE regulation to defined Cullin molecules and phenocopied the antiviral effect of MLN4924.
authors.affiliation: Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Vu Thuy Khanh
authors.initials: VT
authors.lastname: Le-Trilling
authors.affiliation: Medizinisches Proteom-Center, Ruhr Universität Bochum, Bochum, Germany.
authors.forename: Dominik A
authors.initials: DA
authors.lastname: Megger
authors.affiliation: Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Katschinski
authors.affiliation: Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Christine D
authors.initials: CD
authors.lastname: Landsberg
authors.affiliation: Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Meike U
authors.initials: MU
authors.lastname: Rückborn
authors.affiliation: Institute for Virology, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Sha
authors.initials: S
authors.lastname: Tao
authors.affiliation: Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Adalbert
authors.initials: A
authors.lastname: Krawczyk
authors.affiliation: Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Wibke
authors.initials: W
authors.lastname: Bayer
authors.affiliation: Institute for Virology, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Drexler
authors.affiliation: Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Tenbusch
authors.affiliation: Medizinisches Proteom-Center, Ruhr Universität Bochum, Bochum, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Sitek
authors.affiliation: Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Trilling
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D003517:Cyclopentanes / Q000494:pharmacology*; D004266:DNA Virus Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004267:DNA Viruses / Q000378:metabolism*; D006801:Humans; D051379:Mice; D000075687:NEDD8 Protein; D041681:NIH 3T3 Cells; D009975:Orthomyxoviridae / Q000378:metabolism*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology*; D014452:Ubiquitins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D003517:Cyclopentanes; D000075687:NEDD8 Protein; C513172:Nedd8 protein, mouse; D011743:Pyrimidines; D014452:Ubiquitins; C539933:pevonedistat
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