Calcium channel blockers for the treatment of HCMV infections
Human Cytomegalovirus (HCMV) is responsible for severe diseases in immunosuppressed patients and risk of hypertension/atherosclerosis in immunocompetent persons. The current therapy against HCMV, available only to immunosuppressed adult patients, is characterized by serious drawbacks and drug resistant viruses, since all anti-HCMV drugs share a common target. For these reasons, we adopted a drug repurposing (DR) strategy to discover safer new anti-HCMV drugs as well as to identify novel therapeutic targets.
The repurposing strategy consisted in the screening of a library of FDA-approved drugs by a HCMV-specific cell-based assay, that had been validated to identify compounds able to inhibit early phases of the HCMV replicative cycle. Among the selected compounds, there were some calcium channel blockers (CCBs), efonidipine (EFO) and lercanidipine (LERC), both approved for the therapy of hypertension, that were able to impair the in vitro replication of the HCMV laboratory strain (AD169) at micromolar range doses. Importantly, EFO and LERC were effective also against a clinical isolate of HCMV that is resistant to GCV and CDV, and their antiviral potency against HCMV was increased if combined together or with GCV. Moreover, unlike traditional antivirals, EFO and LERC are indicated also for the treatment of HCMV infections in immunocompetent individuals.
- Pre-emptive and/or prophylaxis in immunocompromised patients in combination or with other anti-HCMV agents;
- Treatment of HCMV infections resistant to current anti-HCMV drugs;
- Treatment of HCMV infections in which the risks associated to the use of approved antivirals significantly surpasses the benefits;
- Treatment of HCMV-infected individuals at risk to develop vascular diseases.
- Longer half-life than traditional drugs;
- Less adverse effects;
- Indicated for immunocompetent individuals;
- Effective against a GCV/CDV-resistant HCMV strain;
- Improvement of antiviral potency if combined with traditional drugs;
- Low cost and less time-consuming for their development.