Influenza Virus-Host Interactome Screen as a Platform for Antiviral Drug Development

Watanabe, Tokiko; Kawakami, Eiryo; Shoemaker, Jason E.; Lopes, Tiago J. S.; Matsuoka, Yoshikazu; Tomita, Yuriko; Kozuka‐Hata, Hiroko; Gorai, Takeo; Kuwahara, Tomoko; Takeda, Eiji; Nagata, Atsushi; Takano, Ryo; Kiso, Maki; Yamashita, Makoto; Sakai‐Tagawa, Yuko; Katsura, Hiroaki; Nonaka, N.; Fujii, Hiroko; Fujii, Ken; Sugita, Yukihiko; Noda, Takeshi; Goto, Hideo; Fukuyama, Satoru; Watanabe, Shinji; Neumann, Gabriele; Oyama, Masaaki; Kitano, Hiroaki; Kawaoka, Yoshihiro

doi:10.1016/j.chom.2014.11.002

Cited by 240 publications

(292 citation statements)

References 57 publications

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“…Thirdly, since this drug targets the viral replication by depleting the host guanosine pool, it is unlikely that the virus can develop resistance against it. Many studies are now looking at similar drugs targeting host factors (Watanabe et al, 2014). Fourthly, MPA is an immunomodulator which can dampen the excessive inflammatory response associated with severe influenza.…”

Section: Discussionmentioning

confidence: 99%

Mycophenolic acid, an immunomodulator, has potent and broad-spectrum in vitro antiviral activity against pandemic, seasonal and avian influenza viruses affecting humans

Mok

Chan

et al. 2016

Journal of General Virology

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Section: Discussionmentioning

confidence: 99%

Mycophenolic acid, an immunomodulator, has potent and broad-spectrum in vitro antiviral activity against pandemic, seasonal and avian influenza viruses affecting humans

Mok

Chan

et al. 2016

Journal of General Virology

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“…Influenza viruses commandeer the host cellular machinery for their propagation (5). Targeting of host factors that are critical for viral replication by using small molecular analogues or chemical inhibitors has shown great promise in the development of novel antivirals with broad-spectrum coverage (6).…”

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confidence: 99%

“…To determine whether C646 affects the early steps of the viral life cycle, we infected C646-treated cells with a replication-incompetent PB2-knockout virus, whose PB2-coding region is replaced with that of Renilla luciferase (28). The expression of the Renilla luciferase is an indicator of virus binding, internalization, and limited replication (6). C646 decreased reporter expression in a dose-dependent manner ( Fig.…”

mentioning

confidence: 99%

C646, a Novel p300/CREB-Binding Protein-Specific Inhibitor of Histone Acetyltransferase, Attenuates Influenza A Virus Infection

Zhao

Fukuyama

Sakai‐Tagawa

et al. 2016

Antimicrob Agents Chemother

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e New strategies to develop novel broad-spectrum antiviral drugs against influenza virus infections are needed due to the emergence of antigenic variants and drug-resistant viruses. Here, we evaluated C646, a novel p300/CREB-binding protein-specific inhibitor of histone acetyltransferase (HAT), as an anti-influenza virus agent in vitro and in vivo and explored how C646 affects the viral life cycle and host response. Our studies highlight the value of targeting HAT activity for anti-influenza drug development. Vaccination and antiviral drugs are effective ways to prevent influenza virus infection (1, 2); however, there is an urgent need to screen novel broad-spectrum antiviral drugs with the emergence of antigenic variants and drug-resistant viruses (3, 4). Influenza viruses commandeer the host cellular machinery for their propagation (5). Targeting of host factors that are critical for viral replication by using small molecular analogues or chemical inhibitors has shown great promise in the development of novel antivirals with broad-spectrum coverage (6).Histone acetylation levels are regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) (7). Several HDAC inhibitors that show therapeutic potential for human cancers (8) and nonmalignant diseases (9) have been developed. Roles for HATs in cancer, asthma, chronic obstructive pulmonary disease, and viral infection have been demonstrated (10-12), which indicates that specific HAT inhibitors are potential tools for pharmacological research and may have clinical applications (13). The transcriptional coactivators p300 and CREB-binding protein (CBP) are important members of HAT families possessing HAT activity to influence chromatin activity. p300/CBP HATs are associated with tumorigenesis (14) and the development of many viral diseases (15-18). Several small molecules have been shown to possess p300/CBP HAT inhibitory activity (19-21) and anti-influenza virus properties (22)(23)(24). Recently, the compound C646 was identified as the first selective inhibitor of p300/CBP HATs (25). Here, we evaluated the antiviral effects of C646 on influenza A viruses.C646 showed a 50% cytotoxic concentration (CC 50 ) of 107 M in A549 cells (ATCC). The antiviral potency of C646 in vitro was evaluated based on C646-induced suppression of viral replication. A549 cells were treated with C646 (dimethyl sulfoxide [DMSO] as vehicle) for 10 h and then infected with viruses at an multiplicity of infection (MOI) of 2 or 1. C646 was present throughout the infection. The concentration of DMSO was kept at 0.1%, and 0.4 g/ml tosyl phenylalanyl chloromethyl ketone (TPCK)-trypsin was used to cleave the hemagglutinin for multiple cycles of replication. The cell supernatants were collected for viral titration at the indicated times (26). , and 24 h postinfection (hpi) with a 50% effective concentration (EC 50 ) of 15.8 M (Fig. 1A to E). These findings demonstrate that C646 inhibition of influenza virus replication is not subtype specific.We tested whether C646 directly affects...

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“…It is known that the maximal level of replication and transcription of the influenza virus genome requires not only viral components associated with virions but also some host factors present in infected cells (11,(16)(17)(18)(19)(20)(21)(22). We reconstituted a cell-free viral RNA synthesis system with virion-associated vRNP and nuclear extracts prepared from uninfected HeLa cells (19,23).…”

Section: Importancementioning

confidence: 99%

Pre-mRNA Processing Factor Prp18 Is a Stimulatory Factor of Influenza Virus RNA Synthesis and Possesses Nucleoprotein Chaperone Activity

Minakuchi

Sugiyama

Kato

et al. 2017

J Virol

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The genome of influenza virus (viral RNA [vRNA]) is associated with the nucleoprotein (NP) and viral RNA-dependent RNA polymerases and forms helical viral ribonucleoprotein (vRNP) complexes. The NP-vRNA complex is the biologically active template for RNA synthesis by the viral polymerase. Previously, we identified human pre-mRNA processing factor 18 (Prp18) as a stimulatory factor for viral RNA synthesis using a Saccharomyces cerevisiae replicon system and a single-gene deletion library of Saccharomyces cerevisiae (T. Naito, Y. Kiyasu, K. Sugiyama, A. Kimura, R. Nakano, A. Matsukage, and K. Nagata, Proc Natl Acad Sci USA, 104:18235-18240, 2007, https://doi.org/10.1073/pnas.0705856104). In infected Prp18 knockdown (KD) cells, the synthesis of vRNA, cRNA, and viral mRNAs was reduced. Prp18 was found to stimulate in vitro viral RNA synthesis through its interaction with NP. Analyses using in vitro RNA synthesis reactions revealed that Prp18 dissociates newly synthesized RNA from the template after the early elongation step to stimulate the elongation reaction. We found that Prp18 functions as a chaperone for NP to facilitate the formation of NP-RNA complexes. Based on these results, it is suggested that Prp18 accelerates influenza virus RNA synthesis as an NP chaperone for the processive elongation reaction. IMPORTANCETemplates for viral RNA synthesis of negative-stranded RNA viruses are not naked RNA but rather RNA encapsidated by viral nucleocapsid proteins forming vRNP complexes. However, viral basic proteins tend to aggregate under physiological ionic strength without chaperones. We identified the pre-mRNA processing factor Prp18 as a stimulatory factor for influenza virus RNA synthesis. We found that one of the targets of Prp18 is NP. Prp18 facilitates the elongation reaction of viral polymerases by preventing the deleterious annealing of newly synthesized RNA to the template. Prp18 functions as a chaperone for NP to stimulate the formation of NP-RNA complexes. Based on these results, we propose that Prp18 may be required to maintain the structural integrity of vRNP for processive template reading.

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Influenza Virus-Host Interactome Screen as a Platform for Antiviral Drug Development

Cited by 240 publications

References 57 publications

Mycophenolic acid, an immunomodulator, has potent and broad-spectrum in vitro antiviral activity against pandemic, seasonal and avian influenza viruses affecting humans

Mycophenolic acid, an immunomodulator, has potent and broad-spectrum in vitro antiviral activity against pandemic, seasonal and avian influenza viruses affecting humans

C646, a Novel p300/CREB-Binding Protein-Specific Inhibitor of Histone Acetyltransferase, Attenuates Influenza A Virus Infection

Pre-mRNA Processing Factor Prp18 Is a Stimulatory Factor of Influenza Virus RNA Synthesis and Possesses Nucleoprotein Chaperone Activity

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