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Nedd8-Activating Enzyme Is a Druggable Host Dependency Factor of Human and Mouse Cytomegalovirus

Yulia Alejandra Flores-Martínez1, Vu Thuy Khanh Le-Trilling1, Mirko Trilling1

  • 1Institute for Virology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.

Viruses
|August 28, 2021
PubMed

Insights

The Nedd8-activating enzyme (NAE) and its neddylation process are crucial for cytomegalovirus replication. Inhibiting NAE with drugs like MLN4924 and TAS4464 shows potent antiviral activity, identifying NAE as a druggable host dependency factor.

Area of Science:

  • Virology
  • Molecular Biology
  • Drug Discovery

Background:

  • Human cytomegalovirus (CMV) infections pose significant risks to immunocompromised individuals.
  • CMV manipulates host cell proteasome pathways, including cullin RING ligases (CRLs), for replication.
  • CRL activity is regulated by Nedd8 modification, a process dependent on the Nedd8-activating enzyme (NAE).

Purpose of the Study:

  • To investigate the Nedd8-activating enzyme (NAE) as a potential druggable host dependency factor (HDF) for cytomegaloviruses.
  • To validate the antiviral efficacy of NAE inhibitors against both human and mouse CMV.
  • To confirm the specificity of NAE inhibition in conferring antiviral activity.

Main Methods:

  • Utilized the NAE inhibitor MLN4924 (pevonedistat) and a novel NAE inhibitor, TAS4464.
  • Assessed antiviral activity against human and mouse cytomegalovirus strains.
  • Generated and utilized a cell clone resistant to MLN4924 to evaluate drug specificity.

Main Results:

  • Both MLN4924 and TAS4464 demonstrated potent antiviral activity against cytomegaloviruses.
  • Antiviral activity of both NAE inhibitors was significantly reduced or abolished in the MLN4924-resistant cells.
  • These findings strongly suggest NAE is essential for CMV replication.

Conclusions:

  • The Nedd8-activating enzyme (NAE), the neddylation process, and CRLs represent viable and druggable host dependency factors for cytomegaloviruses.
  • Targeting NAE offers a promising therapeutic strategy for managing CMV infections, particularly in vulnerable populations.
Keywords:
MLN4924Murid herpesvirus 1 (MuHV-1)TAS4464cullin RING ubiquitin ligase (CRL)host dependency factorhuman cytomegalovirus (HCMV)mouse cytomegalovirus (MCMV)nedd8nedd8-activating enzyme (NAE)ubiquitination

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