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Cell Cycle-Dependent Kinase Cdk9 Is a Postexposure Drug Target against Human Adenoviruses
Vibhu Prasad1,2, Maarit Suomalainen1, Silvio Hemmi1
1Institute of Molecular Life Sciences, University of Zurich , Zurich, Switzerland.
Abstract:
Human adenoviruses (HAdVs) infect respiratory, gastrointestinal, and urinary tracts and give rise to eye infections and epidemic keratoconjunctivitis (EKC). They persist in lymphoid tissue and cause morbidity and mortality in immunocompromised people. Treatments with significant postexposure efficacy are not available. Here, we report that inhibition of the cell cycle-dependent kinase 9 (Cdk9) by RNA interference, or the compound flavopiridol, blocked infections with HAdV-C2/5, EKC-causing HAdV-D8/37, and progeny formation in human corneal epithelial and cancer cells. Flavopiridol abrogated the production of the immediate early viral transactivating protein E1A without affecting nuclear import of viral DNA. In morphometric plaque assays, the compound exhibited antiviral efficacy in both pre- and postexposure regimens with therapeutic indexes exceeding 10. The study identifies Cdk9 as a postexposure drug target against adenovirus infections in vitro and suggests that the clinically tested anticancer drug flavopiridol is a candidate for treating adenoviral EKC or adenovirus emergence upon immune suppression.
Insights
Inhibition of cell cycle-dependent kinase 9 (Cdk9) effectively blocks human adenovirus (HAdV) infections, including epidemic keratoconjunctivitis (EKC). The drug flavopiridol shows promise as a postexposure treatment for HAdV infections.
Area of Science:
- Virology
- Molecular Biology
- Drug Discovery
Background:
- Human adenoviruses (HAdVs) cause significant infections, including epidemic keratoconjunctivitis (EKC), and pose risks to immunocompromised individuals.
- Current treatments lack significant postexposure efficacy against HAdV infections.
Purpose of the Study:
- To investigate cell cycle-dependent kinase 9 (Cdk9) as a potential drug target for HAdV infections.
- To evaluate the efficacy of Cdk9 inhibition, specifically using flavopiridol, against HAdV infection and progeny formation.
Main Methods:
- Inhibition of Cdk9 using RNA interference and the compound flavopiridol.
- Infection assays in human corneal epithelial and cancer cells with various HAdV strains (HAdV-C2/5, HAdV-D8/37).
- Morphometric plaque assays to assess antiviral efficacy in pre- and postexposure settings.
Main Results:
- Cdk9 inhibition blocked HAdV infection and viral progeny formation.
- Flavopiridol abrogated the production of the viral transactivating protein E1A without impacting viral DNA nuclear import.
- Antiviral efficacy was demonstrated in both pre- and postexposure regimens with therapeutic indexes exceeding 10.
Conclusions:
- Cdk9 is identified as a viable postexposure drug target against HAdV infections in vitro.
- The clinically tested anticancer drug flavopiridol is a potential candidate for treating adenoviral EKC and emergent HAdV infections in immunocompromised patients.
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