A comprehensive map of the influenza A virus replication cycle

Matsuoka, Yoshikazu; Matsumae, Hiromi; Katoh, Manami; Eisfeld, Amie J.; Neumann, Gabriele; Hase, Takeshi; Ghosh, Samik; Shoemaker, Jason E.; Lopes, Tiago J. S.; Watanabe, Tokiko; Watanabe, Shinji; Fukuyama, Satoru; Kitano, Hiroaki; Kawaoka, Yoshihiro

doi:10.1186/1752-0509-7-97

Cited by 105 publications

(90 citation statements)

References 325 publications

(271 reference statements)

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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).…”

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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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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“…Matsuoka et al [78] attempted to apply another bioinfomatics approach to predict and prioritize host factors that could be therapeutic targets by using a comprehensive map of the influenza virus life cycle called ‘FluMap’ (accessible at http://www.influenza-x.org/flumap/) (Figure 2). FluMap can be used to visualize the entire influenza virus life cycle and was constructed on the basis of information obtained from the literature and publicly available pathway databases.…”

Section: Introductionmentioning

confidence: 99%

“…The authors applied a computational network analysis, called a controllability analysis [79,80], to FluMap to identify host molecules that disregulated the virus replication cycle when their functions were disrupted, resulting in inhibition of virus replication. By using the controllability analysis, Matsuoka and colleagues identified 112 critical host molecules [78]. Further in silico analysis led them to prioritize several important molecules, such as the nuclear pore complex, Akt, PKC, and the Ran/GTPase complex, which are essential and highly connected within the virus-host network [78].…”

Section: Introductionmentioning

confidence: 99%

“…By using the controllability analysis, Matsuoka and colleagues identified 112 critical host molecules [78]. Further in silico analysis led them to prioritize several important molecules, such as the nuclear pore complex, Akt, PKC, and the Ran/GTPase complex, which are essential and highly connected within the virus-host network [78]. Accordingly, these molecules can be prioritized as potential new therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

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Influenza virus–host interactomes as a basis for antiviral drug development

Watanabe

Kawaoka

2015

Current Opinion in Virology

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Currently, antiviral drugs that target specific viral protein functions are available for the treatment of influenza; however, concern regarding the emergence of drug-resistant viruses is warranted, as is the urgent need for new antiviral targets, including non-viral targets, such as host cellular factors. Viruses rely on host cellular functions to replicate, and therefore a thorough understanding of the roles of virus-host interactions during influenza virus replication is essential to develop novel anti-influenza drugs that target the host factors involved in virus replication. Here, we review recent studies that used several approaches to identify host factors involved in influenza virus replication. These studies have permitted the construction of an interactome map of virus-host interactions in the influenza virus life cycle, clarifying the entire life cycle of this virus and accelerating the development of new antiviral drugs with a low propensity for the development of resistance.

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“…39 The influenza A virus replication cycle has been successfully mapped. 40 The virus initiates its life cycle when HA binds to terminal sialic acids on cellular receptors, after which the virus is endocytosed. The low pH of the endosome activates the M2 proton channel in the influenza A viral membrane, which allows protons to enter to the viral core, triggering the fusion of the viral and endosomal membranes with subsequent release of the viral ribonucleoprotein (RNP) to the cytoplasm and its subsequent transport to the nucleus.…”

Section: Sa and Asa As Precursors For Osp Synthesismentioning

confidence: 99%

Current perspectives on applications of shikimic and aminoshikimic acids in pharmaceutical chemistry

Quiroz¹,

Carmona²,

Bolívar³

et al. 2014

RRMC

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Aromatic metabolism comprises the shikimic acid (SA) and the aminoshikimic acid (ASA) pathways. The SA pathway is the common route for the biosynthesis of aromatic amino acids and other metabolites in bacteria, higher plants, fungi, and Apicomplexa parasites, but this pathway is absent in mammals. A variant of the SA pathway known as the ASA pathway branches off from the normal pathway in some bacteria, and its final product, 3-amino-5-hydroxybenzoic acid, is the precursor for many aminoglycoside antibiotics such as kanamycin, neomycin, butirosin, and spectinomycin. The SA pathway includes the key intermediate SA, which is the precursor for the chemical synthesis of the drug oseltamivir phosphate, known commercially as Tamiflu ® , an efficient inhibitor of the neuraminidase enzyme of the seasonal influenza viruses types A and B, avian influenza virus H5N1, and human influenza virus H1N1. Meanwhile, the intermediate of the ASA pathway, ASA, is an attractive candidate for use as the core scaffold for the synthesis of combinatorial libraries and is a potential alternative to SA as a precursor for oseltamivir phosphate synthesis. In this review, we discuss the relevance of the key intermediates SA and ASA as scaffold molecules for the synthesis of diverse chemicals. We highlight the current and potential pharmaceutical applications of these molecules and discuss the main strategies for the production of these aromatic compounds from natural sources and the application of metabolic engineering strategies in diverse bacterial strains for production through biotechnological processes.

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A comprehensive map of the influenza A virus replication cycle

Cited by 105 publications

References 325 publications

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

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

Influenza virus–host interactomes as a basis for antiviral drug development

Current perspectives on applications of shikimic and aminoshikimic acids in pharmaceutical chemistry

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