A new role for an established drug - are clinically approved therapeutics suitable for HCMV treatment?

HCMV is a member of the herpes virus family and has spread throughout the world for thousands of years. In people with a healthy immune system, infection is usually mild and asymptomatic. Like other herpes viruses, HCMV can cause a chronic infection that results in viral persistence for a lifetime. However, in immunocompromised people, such as organ transplant recipients and AIDS patients, HCMV infection can lead to devastating complications and an increased risk of death. 

Several drugs are currently available to inhibit the replication of the virus. However, all approved drugs have limitations due to side effects such as nephrotoxicity and the emergence of resistant strains of HCMV. 

As HCMV relies on cellular kinases and a viral kinase for replication, inhibiting these has long been discussed as a promising antiviral therapy. A specific inhibitor, maribavir (MBV), was developed, but failed to perform well in clinical trials. A research team led by Georgios Vavouras Syrigos and Prof. Michael Schindler hypothesised that a panel of novel cyclin-dependent kinase 4/6 (CDK4/6) inhibitors might be promising drug candidates against HCMV. These CDK inhibitors have a key advantage: they are FDA-approved drugs with known toxicity and pharmacokinetics and are already used in breast cancer therapy. 

Together with colleagues from the University of Berlin, the team has shown that a specific CDK4/6 inhibitor called abemaciclib is very effective in suppressing HCMV infections. The researchers' results also show that the inhibitor blocks the function of the viral kinase called pUL97 more effectively than maribavir or the other CDK4/6 inhibitors. HCMV normally uses pUL97 to disable the antiviral activity of a host defence protein called SAMHD1. Abemaciclib prevents this step. As a result, the virus cannot switch off the antiviral defence mechanisms and viral replication is inhibited. The results pave the way for the evaluation of abemaciclib as a novel therapeutic option against HCMV in certain patient populations or for the treatment of infections with multi-resistant HCMV strains.

The results of the study have now been published in the journal Antiviral Research. The paper is available at:

https://www.sciencedirect.com/science/article/abs/pii/S0166354223001675.