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CDK9 inhibitor FIT-039 prevents replication of multiple DNA viruses
Makoto Yamamoto, … , Takamitsu Hosoya, Masatoshi Hagiwara
Makoto Yamamoto, … , Takamitsu Hosoya, Masatoshi Hagiwara
Published August 1, 2014; First published July 8, 2014
Citation Information: J Clin Invest. 2014;124(8):3479-3488. https://doi.org/10.1172/JCI73805.
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Categories: Research Article Virology

CDK9 inhibitor FIT-039 prevents replication of multiple DNA viruses

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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

Makoto Yamamoto, Hiroshi Onogi, Isao Kii, Suguru Yoshida, Kei Iida, Hiroyuki Sakai, Minako Abe, Toshiaki Tsubota, Nobutoshi Ito, Takamitsu Hosoya, Masatoshi Hagiwara

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Figure 5

FIT-039 inhibited the replication of ACV-resistant HSV-1.

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FIT-039 inhibited the replication of ACV-resistant HSV-1.
(A) FIT-039 su...
(A) FIT-039 suppressed the plaque formation caused by the ACV-resistant HSV-1 infection in a dose-dependent manner. Plaque reduction assay was performed in Vero cells treated with the indicated concentrations of FIT-039, ACV, and GCV. Living cells were stained with crystal violet, and the number of plaques was then counted. ACV and GCV did not suppress the plaque formation. Each point represents the average ± SD of the results from 3 experiments preformed in duplicate. *P < 0.001, versus DMSO treatment, Student’s t test. (B and C) The scratched skins of mice were infected intracutaneously with ACV-resistant HSV-1 and were then treated with ointments containing the indicated concentrations of FIT-039. Five mice were assigned to each experimental group. (B) The lesion score and (C) survival rate were determined. (B) Representative photographs of the infected mice 7 days after infection are shown. The ACV ointment did not suppress skin lesions or lethality. Each point represents the average of the results (n = 5).
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