B. Mercorelli, A. Luganini, M. Celegato
Feb 1, 2018
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Influential Citations
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Journal
Antiviral Research
Abstract
Abstract Currently, there are no therapeutic alternatives to DNA polymerase inhibitors to treat human cytomegalovirus (HCMV) infections, a major threat for immunocompromised patients and pregnant women. Here, we explored the potential to repurpose manidipine dihydrochloride (MND), a calcium antagonist clinically approved to treat hypertension, as a new anti‐HCMV agent. MND emerged in a previous drug repurposing screen to find early inhibitors of HCMV replication, and now we confirm that it inhibits in the low micromolar range the replication of different HCMV strains, including clinical isolates and viruses resistant to approved DNA polymerase inhibitors. The antiviral activity of MND is specific for HCMV over different both DNA and RNA viruses. Further experiments in HCMV‐infected cells testing the effects of MND on viral DNA synthesis and viral proteins expression revealed that it halts the progression of the virus cycle prior to viral DNA replication and E genes expression, but after IE proteins expression. According to these results, we observed that the overall antiviral activity of MND involves a specific interference with the transactivating functions of the viral Immediate‐Early 2 (IE‐2) protein, an essential viral transcription factor required for the progression of HCMV replication. Given that the inhibitory concentration against HCMV is in the range of clinically relevant concentrations of MND in humans, and the mechanism of action differs from that of the other available therapeutics, this already approved drug is an attractive candidate for repurposing in alternative anti‐HCMV therapeutic protocols. HighlightsWe disclose the repurposing potential of the anti‐hypertensive drug manidipine as an antiviral against HCMV.Manidipine specifically inhibits different HCMV strains but no other DNA and RNA viruses in the low micromolar range.Manidipine prevents viral DNA synthesis and E and L viral genes expression.The anti‐HCMV activity of manidipine stems from interference with the transactivating functions of the viral IE2 protein.The mechanism of manidipine differs from that of current HCMV drugs, thus it could be repurposed alone or in combination.