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甲型流感病毒的RNA聚合酶由PB1、PB2和PA 三个亚基组成,在病毒的生命周期中负责行使病毒基因组的转录与复制等多方面功能. 甲型流感病毒由于频繁变异,导致其对传统抗病毒药物的敏感性降低,因此开发疗效好、针对性强、毒性低的新型抗病毒药物已成为当前亟待解决的问题.由于RNA聚合酶是甲型流感病毒生命周期重要的调控蛋白,并且编码聚合酶各亚基的基因序列具有高度保守性,故成为当前抗病毒药物的重要靶点. 相似文献
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Masaki Shoji Etsuhisa Takahashi Dai Hatakeyama Yuma Iwai Yuka Morita Riku Shirayama Noriko Echigo Hiroshi Kido Shigeo Nakamura Tadahiko Mashino Takeshi Okutani Takashi Kuzuhara 《PloS one》2013,8(6)
The H1N1 influenza A virus, which originated in swine, caused a global pandemic in 2009, and the highly pathogenic H5N1 avian influenza virus has also caused epidemics in Southeast Asia in recent years. Thus, the threat from influenza A remains a serious global health issue, and novel drugs that target these viruses are highly desirable. Influenza A RNA polymerase consists of the PA, PB1, and PB2 subunits, and the N-terminal domain of the PA subunit demonstrates endonuclease activity. Fullerene (C60) is a unique carbon molecule that forms a sphere. To identify potential new anti-influenza compounds, we screened 12 fullerene derivatives using an in vitro PA endonuclease inhibition assay. We identified 8 fullerene derivatives that inhibited the endonuclease activity of the PA N-terminal domain or full-length PA protein in vitro. We also performed in silico docking simulation analysis of the C60 fullerene and PA endonuclease, which suggested that fullerenes can bind to the active pocket of PA endonuclease. In a cell culture system, we found that several fullerene derivatives inhibit influenza A viral infection and the expression of influenza A nucleoprotein and nonstructural protein 1. These results indicate that fullerene derivatives are possible candidates for the development of novel anti-influenza drugs. 相似文献
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Takahito Kashiwagi Koyu Hara Yoko Nakazono Yusaku Uemura Yoshihiro Imamura Nobuyuki Hamada Hiroshi Watanabe 《PloS one》2014,9(12)
Background
Influenza A virus has a RNA-dependent RNA polymerase (RdRp) that is composed of three subunits (PB1, PB2 and PA subunit), which assemble with nucleoproteins (NP) and a viral RNA (vRNA) to form a RNP complex in the host nucleus. Recently, we demonstrated that the combination of influenza ribonucleoprotein (RNP) components is important for both its assembly and activity. Therefore, we questioned whether the inhibition of the RNP combination via an incompatible component in the RNP complex could become a methodology for an anti-influenza drug.Methodology/Principal Findings
We found that a H5N1 PB2 subunit efficiently inhibits H1N1 RNP assembly and activity. Moreover, we determined the domains and important amino acids on the N-terminus of the PB2 subunit that are required for a strong inhibitory effect. The NP binding site of the PB2 subunit is important for the inhibition of RNP activity by another strain. A plaque assay also confirmed that a fragment of the PB2 subunit could inhibit viral replication.Conclusions/Significance
Our results suggest that the N-terminal fragment of a PB2 subunit becomes an inhibitor that targets influenza RNP activity that is different from that targeted by current drugs such as M2 and NA inhibitors. 相似文献8.
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Nguyen Trong Binh Chitose Wakai Atsushi Kawaguchi Kyosuke Nagata 《Biochemical and biophysical research communications》2014
The influenza virus PB1 protein functions as a catalytic subunit of the viral RNA-dependent RNA polymerase and contains the highly conserved motifs of RNA-dependent RNA polymerases together with putative nucleotide-binding sites. PB1 also binds to viral genomic RNAs and its replicative intermediates through the promoter regions. The detail function and interplay between functional domains are not clarified although a part of structures and functions of PB1 have been clarified. In this study, we analyzed the function of PB1 subunit in the sense of nucleotide recognition using ribavirin, which is a nucleoside analog and inhibits viral RNA synthesis of many RNA viruses including influenza virus. We screened ribavirin-resistant PB1 mutants from randomly mutated PB1 cDNA library using a mini-replicon assay, and we identified a single mutation at the amino acid position 27 of PB1 as an important residue for the nucleotide recognition. 相似文献
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Influenza viruses cause a significant level of morbidity and mortality in the population every year. Their resistance to current anti-influenza drugs increases the difficulty of flu treatment. Thus, development of new anti-influenza drugs is necessary in regards of prevent the tragedy of influenza pandemic. The Polymerase basic protein 2 (PB2) subunit of influenza virus RNA polymerase is one of potential targets for new drugs because the binding of PB2 with the 5' cap of the host pre-mRNAs is the initial step of the virus' protein synthesis. In this study, we compared the binding potency of PB2 cap binding domain with two small molecules, i.e., RO and PPT28, with that of PB2 with cap analog m7GTP. The calculated binding energies showed that RO and PPT28 had higher binding affinity with PB2. Further interaction analysis showed that the important parts for binding were the five- and six-member heterocyclic rings (the 6/5-member rings) of small molecules, as well as the hydrophobic parts of RO and PPT28 which had good interactions with the hydrophobic residues in the binding cavity. Thus, RO and PPT28 are two potential anti-influenza drugs targeted PB2, which may inhibit the growth of influenza virus by competitively binding with the cap structure binding domain of PB2. 相似文献
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Identification of Hsp90 as a stimulatory host factor involved in influenza virus RNA synthesis 总被引:12,自引:0,他引:12
Momose F Naito T Yano K Sugimoto S Morikawa Y Nagata K 《The Journal of biological chemistry》2002,277(47):45306-45314
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Ghanem A Mayer D Chase G Tegge W Frank R Kochs G García-Sastre A Schwemmle M 《Journal of virology》2007,81(14):7801-7804
The assembly of the polymerase complex of influenza A virus from the three viral polymerase subunits PB1, PB2, and PA is required for viral RNA synthesis. We show that peptides which specifically bind to the protein-protein interaction domains in the subunits responsible for complex formation interfere with polymerase complex assembly and inhibit viral replication. Specifically, we provide evidence that a 25-amino-acid peptide corresponding to the PA-binding domain of PB1 blocks the polymerase activity of influenza A virus and inhibits viral spread. Targeting polymerase subunit interactions therefore provides a novel strategy to develop antiviral compounds against influenza A virus or other viruses. 相似文献
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The active sites of the influenza cap-dependent endonuclease are on different polymerase subunits 总被引:3,自引:0,他引:3
The cap-dependent endonuclease of the influenza viral RNA polymerase, which produces the capped RNA primers that initiate viral mRNA synthesis, is comprised of two active sites, one for cap binding and one for endonuclease cleavage.We identify the amino acid sequences that constitute these two active sites and demonstrate that they are located on different polymerase subunits. Binding of the 5' terminal sequence of virion RNA (vRNA) to the polymerase activates a tryptophan-rich, cap-binding sequence on the PB2 subunit. At least one of the tryptophans functions in cap binding, indicating that this active site is probably similar to that of other known cap-binding proteins. Endonuclease cleavage, which is activated by the subsequent binding of the 3' terminal sequence of vRNA, resides in a PB1 sequence that contains three essential acidic amino acids, similar to the active sites of other enzymes that cut polynucleotides to produce 3'-OH ends. These results, coupled with those of our previous study, provide a molecular map of the five known essential active sites of the influenza viral polymerase. 相似文献
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《Bioorganic & medicinal chemistry letters》2019,29(13):1609-1613
PB2 is an important subunit of influenza RNA-dependent RNA polymerase (RdRP) and has been recognized as a promising target for the treatment of influenza. We herein report the discovery of a new series of PB2 inhibitors containing the skeleton 5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazin-2(1H)-one. Compound 12b is the most potent one, which showed KD values of 0.11 μM and 0.19 μM in surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) assays, respectively. In antiviral activity and cellular cytotoxicity assays, compound 12b showed an EC50 value of 1.025 μM and a CC50 value greater than 100 μM. Molecular docking was also used to predict the binding mode of 12b with PB2. Collectively, this study provides a promising lead compound for subsequent anti-influenza drug discovery targeting PB2. 相似文献