Broad and potent antiviral activity of the NAE inhibitor MLN4924

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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Scientific reports 2016-02, Vol.6 (1), p.19977-19977, Article 19977
Hauptverfasser: 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: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep19977