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Published on: May 15, 2014
Ciclopirox suppresses poxvirus replication by targeting iron metabolism
Anil Pant1, Djamal Brahim Belhaouari1, Lara Dsouza1
1Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX, USA.
Abstract:
Poxviruses remain a significant global health concern, necessitating the development of novel antiviral strategies. Through high-throughput screening, we previously identified ciclopirox (CPX), an FDA-approved antifungal, as a hit that inhibits vaccinia virus (VACV) replication. Here, we further characterized its antiviral activity and mechanism of action using human primary fibroblasts. CPX significantly reduced VACV titers without reducing host cell viability, with an EC50 in the sub-micromolar range and a CC50 >500 μM. Rescue experiments demonstrated that CPX inhibits viral replication primarily through chelation of intracellular Fe3+ and, to a lesser extent, Fe2+, as evidenced by partial restoration of viral replication with ferric ammonium citrate supplementation. Furthermore, overexpression of the iron-dependent enzymes RRM2 and the VACV-encoded F4L reduced the inhibitory effect of CPX, indicating that these host and viral proteins are affected by CPX treatment. Moreover, CPX treatment also suppressed cowpox virus and monkeypox (mpox) virus replication in vitro. It also reduced VACV titers in ex vivo mouse lung tissue. These findings highlight host iron metabolism as a critical determinant of poxvirus replication and support repurposing CPX as a broad-spectrum orthopoxvirus antiviral candidate.
Insights
Ciclopirox (CPX), an antifungal drug, effectively inhibits vaccinia virus (VACV) replication by chelating iron. This repurposed drug shows promise as a broad-spectrum antiviral against orthopoxviruses like monkeypox virus.
Area of Science:
- Virology
- Infectious Diseases
- Drug Discovery
Background:
- Poxviruses pose a significant global health threat, driving the need for new antiviral therapies.
- High-throughput screening identified ciclopirox (CPX), an FDA-approved antifungal, as a potential inhibitor of vaccinia virus (VACV) replication.
Purpose of the Study:
- To characterize the antiviral activity and mechanism of action of ciclopirox (CPX) against poxviruses.
- To evaluate CPX as a potential broad-spectrum antiviral agent for orthopoxvirus infections.
Main Methods:
- Human primary fibroblasts were used to assess CPX's antiviral efficacy and cytotoxicity.
- Rescue experiments involving iron supplementation and overexpression of iron-dependent enzymes were conducted.
- Antiviral activity was tested against cowpox virus, monkeypox virus, and in ex vivo mouse lung tissue.
Main Results:
- CPX demonstrated significant inhibition of VACV replication with low EC50 and high CC50 values, indicating a good safety profile.
- The primary mechanism of action involves the chelation of intracellular iron (Fe3+ and Fe2+).
- CPX effectively suppressed cowpox and monkeypox virus replication in vitro and VACV in ex vivo mouse lung tissue.
Conclusions:
- Host iron metabolism is crucial for poxvirus replication.
- Ciclopirox (CPX) is a potent inhibitor of orthopoxvirus replication, acting via iron chelation.
- CPX represents a promising candidate for repurposing as a broad-spectrum antiviral against poxviruses, including monkeypox virus.
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