Ciclopirox suppresses poxvirus replication by targeting iron metabolism

Area of Science:

• Virology
• Antimicrobial Research
• Drug Discovery

Background:

• Poxviruses, including vaccinia virus (VACV), pose significant global health threats, driving the need for new antiviral therapies.
• High-throughput screening identified ciclopirox (CPX), an FDA-approved antifungal, as a potential inhibitor of VACV replication.

Purpose of the Study:

• To characterize the antiviral activity and mechanism of action of ciclopirox (CPX) against vaccinia virus (VACV).
• To evaluate CPX's efficacy against other orthopoxviruses and in ex vivo models.

Main Methods:

• Human primary fibroblasts were used to assess CPX's antiviral activity (EC50) and cytotoxicity (CC50).
• Rescue experiments with iron supplementation and overexpression of iron-dependent enzymes (RRM2, F4L) elucidated the mechanism of action.
• In vitro assays were performed on cowpox virus and monkeypox (mpox) virus, and ex vivo mouse lung tissue was used to test CPX efficacy.

Main Results:

• CPX demonstrated potent inhibition of VACV replication (sub-micromolar EC50) with low host cell toxicity (CC50 > 500 μM).
• The antiviral effect is primarily attributed to the chelation of intracellular iron (Fe3+ and Fe2+).
• CPX suppressed replication of cowpox virus and mpox virus in vitro and reduced VACV titers in ex vivo mouse lung tissue.

Conclusions:

• Ciclopirox (CPX) exhibits broad-spectrum antiviral activity against orthopoxviruses by targeting host iron metabolism.
• CPX represents a promising therapeutic candidate for treating poxvirus infections, including mpox virus.