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Filociclovir Is a Potent In Vitro and In Vivo Inhibitor of Human Adenoviruses
Karoly Toth1, Islam T M Hussein2, Ann E Tollefson1
1Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
Abstract:
Human adenovirus (HAdV) infection is common in the general population and can cause a range of clinical manifestations, among which pneumonia and keratoconjunctivitis are the most common. Although HAdV infections are mostly self-limiting, infections in immunocompromised individuals can be severe. No antiviral drug has been approved for treating adenoviruses. Filociclovir (FCV) is a nucleoside analogue which has successfully completed phase I human clinical safety studies and is now being developed for treatment of human cytomegalovirus (HCMV)-related disease in immunocompromised patients. In this report, we show that FCV is a potent broad-spectrum inhibitor of HAdV types 4 to 8, with 50% effective concentrations (EC50s) ranging between 1.24 and 3.6 μM and a 50% cytotoxic concentration (CC50) of 100 to 150 μM in human foreskin fibroblasts (HFFs). We also show that the prophylactic oral administration of FCV (10 mg/kg of body weight) 1 day prior to virus challenge and then daily for 14 days to immunosuppressed Syrian hamsters infected intravenously with HAdV6 was sufficient to prevent morbidity and mortality. FCV also mitigated tissue damage and inhibited virus replication in the liver. The 10-mg/kg dose had similar effects even when the treatment was started on day 4 after virus challenge. Furthermore, FCV administered at the same dose after intranasal challenge with HAdV6 partially mitigated body weight loss but significantly reduced pathology and virus replication in the lung. These findings suggest that FCV could potentially be developed as a pan-adenoviral inhibitor.
Insights
Filociclovir (FCV) shows promise as a broad-spectrum antiviral for human adenovirus (HAdV) infections. This study demonstrates FCV
Area of Science:
- Virology
- Antiviral Research
- Immunocompromised Patient Care
Background:
- Human adenovirus (HAdV) infections are prevalent, causing conditions like pneumonia and keratoconjunctivitis.
- Severe HAdV infections occur in immunocompromised individuals, with no approved antiviral treatments.
- Filociclovir (FCV), a nucleoside analogue, has completed Phase I safety trials for human cytomegalovirus (HCMV) treatment.
Purpose of the Study:
- To evaluate Filociclovir (FCV) as a potential broad-spectrum antiviral agent against human adenovirus (HAdV).
- To assess the efficacy of FCV in preventing and treating HAdV infection in an animal model.
Main Methods:
- In vitro testing of FCV against HAdV types 4-8 using human foreskin fibroblasts (HFFs) to determine EC50 and CC50 values.
- In vivo studies using immunosuppressed Syrian hamsters infected with HAdV6.
- FCV administered orally prophylactically and therapeutically via intravenous and intranasal challenge routes.
Main Results:
- FCV demonstrated potent broad-spectrum inhibition of HAdV types 4-8 in vitro (EC50: 1.24–3.6 μM).
- Prophylactic oral FCV (10 mg/kg) in hamsters prevented HAdV6-induced morbidity and mortality, reducing liver pathology and viral replication.
- Therapeutic FCV administration (starting day 4 post-challenge) and intranasal treatment also mitigated disease, pathology, and viral load in the lung.
Conclusions:
- Filociclovir (FCV) is a potent inhibitor of multiple human adenovirus (HAdV) types in vitro.
- FCV demonstrates significant therapeutic and prophylactic efficacy against HAdV6 infection in an immunocompromised hamster model.
- These findings support the potential development of FCV as a pan-adenoviral antiviral therapy.
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