Cell Cycle-Dependent Kinase Cdk9 Is a Postexposure Drug Target against Human Adenoviruses.

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.
Authors	Vibhu Prasad, Maarit Suomalainen, Silvio Hemmi, Urs F Greber
Journal	ACS infectious diseases (ACS Infect Dis) Vol. 3 Issue 6 Pg. 398-405 (06 09 2017) ISSN: 2373-8227 [Electronic] United States
PMID	28434229 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Adenovirus E1A Proteins Antiviral Agents Flavonoids Piperidines RNA, Small Interfering alvocidib CDK9 protein, human Cyclin-Dependent Kinase 9
Topics	Adenovirus E1A Proteins (antagonists & inhibitors, biosynthesis, genetics) Adenoviruses, Human (drug effects, genetics, metabolism) Antiviral Agents (pharmacology) Cell Cycle (drug effects, genetics) Cell Line Cornea (drug effects, pathology, virology) Cyclin-Dependent Kinase 9 (antagonists & inhibitors, genetics, metabolism) Dose-Response Relationship, Drug Epithelial Cells (drug effects, pathology, virology) Flavonoids (pharmacology) Gene Expression Regulation HeLa Cells Host-Pathogen Interactions Humans Piperidines (pharmacology) RNA, Small Interfering (genetics, metabolism)

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