title: CDK9 inhibitor FIT-039 prevents replication of multiple DNA viruses.
abstract: A wide range of antiviral drugs is currently available; however, drug-resistant viruses have begun to emerge and represent a potential public health risk. Here, we explored the use of compounds that inhibit or interfere with the action of essential host factors to prevent virus replication. In particular, we focused on the cyclin-dependent kinase 9 (CDK9) inhibitor, FIT-039, which suppressed replication of a broad spectrum of DNA viruses through inhibition of mRNA transcription. Specifically, FIT-039 inhibited replication of herpes simplex virus 1 (HSV-1), HSV-2, human adenovirus, and human cytomegalovirus in cultured cells, and topical application of FIT-039 ointment suppressed skin legion formation in a murine HSV-1 infection model. FIT-039 did not affect cell cycle progression or cellular proliferation in host cells. Compared with the general CDK inhibitor flavopiridol, transcriptome analyses of FIT-039-treated cells revealed that FIT-039 specifically inhibited CDK9. Given at concentrations above the inhibitory concentration, FIT-039 did not have a cytotoxic effect on mammalian cells. Importantly, administration of FIT-039 ameliorated the severity of skin lesion formation in mice infected with an acyclovir-resistant HSV-1, without noticeable adverse effects. Together, these data indicate that FIT-039 has potential as an antiviral agent for clinical therapeutics.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Onogi
authors.forename: Isao
authors.initials: I
authors.lastname: Kii
authors.forename: Suguru
authors.initials: S
authors.lastname: Yoshida
authors.forename: Kei
authors.initials: K
authors.lastname: Iida
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sakai
authors.forename: Minako
authors.initials: M
authors.lastname: Abe
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tsubota
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Ito
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Hosoya
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hagiwara
mesh_terms: D000212:Acyclovir / Q000494:pharmacology; D000260:Adenoviruses, Human / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors*; D003587:Cytomegalovirus / Q000187:drug effects / Q000502:physiology; D004267:DNA Viruses / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D024882:Drug Resistance, Viral; D005419:Flavonoids / Q000494:pharmacology; D057809:HEK293 Cells; D006367:HeLa Cells; D006561:Herpes Simplex / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000502:physiology; D018258:Herpesvirus 2, Human / Q000187:drug effects / Q000502:physiology; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D014158:Transcription, Genetic / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; C000595272:FIT-039; D005419:Flavonoids; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C077990:alvocidib; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9; D000212:Acyclovir