Broad and potent antiviral activity of the NAE inhibitor MLN4924

Le-Trilling VTK, Megger DA, Katschinski B, Landsberg CD, Rueckborn MU, Tao S, Krawczyk A, Bayer W, Drexler I, Tenbusch M, Sitek B, Trilling M (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Scientific Reports Nature Publishing Group: Open Access Journals - Option B

Book Volume: 6

Pages Range: 19977

DOI: 10.1038/srep19977

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 with CRIS profile

Matthias Tenbusch Professur für Genbasierte Immunisierungsverfahren

Involved external institutions

Universität Duisburg-Essen (UDE) DE Germany (DE) Ruhr-Universität Bochum (RUB) DE Germany (DE) Heinrich-Heine-Universität Düsseldorf DE Germany (DE)

How to cite

APA:

Le-Trilling, V.T.K., Megger, D.A., Katschinski, B., Landsberg, C.D., Rueckborn, M.U., Tao, S.,... Trilling, M. (2016). Broad and potent antiviral activity of the NAE inhibitor MLN4924. Scientific Reports, 6, 19977. https://doi.org/10.1038/srep19977

MLA:

Le-Trilling, Vu Thuy Khanh, et al. "Broad and potent antiviral activity of the NAE inhibitor MLN4924." Scientific Reports 6 (2016): 19977.

BibTeX: Download