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.