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

by Selleckchem | Sep 02 2023

Human cytomegalovirus causes diseases in individuals with insufficient immunity. Cytomegaloviruses exploit the ubiquitin proteasome pathway to manipulate the proteome of infected cells. The proteasome degrades ubiquitinated proteins. The family of cullin RING ubiquitin ligases (CRL) regulates the stability of numerous important proteins. If the cullin within the CRL is modified with Nedd8 ("neddylated"), the CRL is enzymatically active, while CRLs lacking Nedd8 modifications are inactive. The Nedd8-activating enzyme (NAE) is indispensable for neddylation. By binding to NAE and inhibiting neddylation, the drug MLN4924 (pevonedistat) causes CRL inactivation and stabilization of CRL target proteins. We showed that MLN4924 elicits potent antiviral activity against cytomegaloviruses, suggesting that NAE might be a druggable host dependency factor (HDF). However, MLN4924 is a nucleoside analog related to AMP, and the antiviral activity of MLN4924 may have been influenced by off-target effects in addition to NAE inhibition. To test if NAE is indeed an HDF, we assessed the novel NAE inhibitor TAS4464 and observed potent antiviral activity against mouse and human cytomegalovirus. Additionally, we raised an MLN4924-resistant cell clone and showed that MLN4924 as well as TAS4464 lose their antiviral activity in these cells. Our results indicate that NAE, the neddylation process, and CRLs are druggable HDFs of cytomegaloviruses.

Comments:

That is an interesting research finding. It appears that the drug MLN4924 (pevonedistat) and the novel NAE inhibitor TAS4464 have shown potent antiviral activity against cytomegaloviruses. This suggests that NAE (Nedd8-activating enzyme), the neddylation process, and CRLs (cullin RING ubiquitin ligases) could be potential targets for developing drugs against cytomegalovirus infections.

The study showed that MLN4924, by inhibiting NAE and preventing neddylation, causes inactivation of CRLs and stabilization of CRL target proteins. This leads to potent antiviral activity against cytomegaloviruses. However, since MLN4924 is structurally related to AMP (adenosine monophosphate), there might be off-target effects influencing its antiviral activity. Therefore, to confirm if NAE is indeed a druggable host dependency factor (HDF) for cytomegaloviruses, the researchers tested the novel NAE inhibitor TAS4464 and observed similar potent antiviral activity against mouse and human cytomegalovirus.

Furthermore, the researchers raised an MLN4924-resistant cell clone and demonstrated that both MLN4924 and TAS4464 lost their antiviral activity in these cells. This suggests that the antiviral activity of these drugs is specifically related to their inhibition of NAE and the neddylation process.

Overall, these findings indicate that NAE, the neddylation process, and CRLs are potential targets for developing drugs against cytomegalovirus infections. Further research and development in this area could lead to the discovery of more effective treatments for cytomegalovirus-related diseases in individuals with compromised immunity.