Broad and potent antiviral activity of the NAE inhibitor MLN4924

• Published in: Scientific reports 2016-02, Vol.6 (1), p.19977-19977, Article 19977
• Main Authors: Le-Trilling, Vu Thuy Khanh, Megger, Dominik A., Katschinski, Benjamin, Landsberg, Christine D., Rückborn, Meike U., Tao, Sha, Krawczyk, Adalbert, Bayer, Wibke, Drexler, Ingo, Tenbusch, Matthias, Sitek, Barbara, Trilling, Mirko
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 38/109; 38/77; 631/326/596/1553; 631/326/596/2557; 631/326/596/2558; 82/58; 82/80; Animals; Antagonism; Antiviral activity; Antiviral Agents - pharmacology; Clinical isolates; Cullin; Cyclopentanes - pharmacology; Cytomegalovirus; DNA Virus Infections - drug therapy; DNA Virus Infections - metabolism; DNA Virus Infections - pathology; DNA Viruses - metabolism; Drug resistance; Genomes; Glycoproteins; Herpes simplex; Humanities and Social Sciences; Humans; IE1 protein; Influenza; Interferon; Mice; multidisciplinary; Multidrug resistance; NEDD8 Protein; NIH 3T3 Cells; Orthomyxoviridae - metabolism; Orthomyxoviridae Infections - drug therapy; Orthomyxoviridae Infections - metabolism; Orthomyxoviridae Infections - pathology; Proteomes; Pyrimidines - pharmacology; Science; Ubiquitin; Ubiquitins - antagonists & inhibitors; Ubiquitins - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep19977

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.