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    Baloxavir (Xofluza; BXA; S033447)
    Baloxavir (Xofluza; BXA; S033447)

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    产品仅用于科学研究,不针对患者销售
    数量: - + 件(库存件)
    InvivoChem目录号 #: V0094
    CAS号码 #: 1985605-59-1 (Baloxavir); 纯度 ≥98%

    Description: Baloxavir (trade name Xofluza; also known as Baloxavir acid, BXA,or S-033447), derived from the prodrug baloxavir marboxil (BXM), is an orally available small molecule inhibitor of the cap-dependent endonuclease. It is an antiviral drug developed by Roche and Shionogi as an anti-influenza agent for treatment of influenza A and influenza B flu. As of 2018, it was approved for clinical use in Japan and in the United States. Baloxavir was discovered by rational molecular design based on the two-metal pharmacophore concept for dolutegravir (DTG), a strand transfer inhibitor of human immunodeficiency virus (HIV) integrase. Baloxavir potently and selectively inhibits the cap-dependent endonuclease within the polymerase PA subunit of influenza A and B viruses. In February 2018, baloxavir received its first global approval in Japan for the treatment of influenza A or B virus infections. Phase III development is underway in the USA, EU and other countries for this indication.The drug blocks influenza virus proliferation by inhibiting the initiation of mRNA synthesis. In clinical trials, single doses of Baloxavir profoundly decrease viral titers as well as alleviating influenza symptoms. 

    References:  2018 Jun 25;8(1):9633;  2018 Apr;78(6):693-697; WO 2017104691 A1.

    Related CAS: 1985606-14-1 (baloxavir marboxil)   1985605-59-1 (Baloxavir)

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    Molecular Weight (MW) 483.49
    Formula C₂₄H₁₉F₂N₃O₄S
    CAS No. 1985605-59-1 (Baloxavir); 
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 10mM
    Water: N/A
    Ethanol: N/A
    Chemical Name ({(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl]-6,8-dioxo-3,4,6,8,12,12ahexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)
    SynonymsTrade name Xofluza; Baloxavir acid; BXA; Baloxavir marboxil; S-033447; S 033447; S033447; Baloxavir;
    SMILES CodeO=C1N2[C@](COCC2)([H])N([C@@H]3C4=CC=CC=C4SCC5=C(F)C(F)=CC=C35)N6C1=C(O)C(C=C6)=O


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    In Vitro

    In vitro activity: Baloxavir (trade name Xofluza; Baloxavir acid or BXA) is an orally available small molecule inhibitor of the cap-dependent endonuclease developed by Roche and Shionogi. It potently and selectively inhibits the cap-dependent endonuclease within the polymerase PA subunit of influenza A and B viruses. In February 2018, baloxavir received its first global approval in Japan for the treatment of influenza A or B virus infections. Phase III development is underway in the USA, EU and other countries for this indication.The drug blocks influenza virus proliferation by inhibiting the initiation of mRNA synthesis. PA I38T substitution is a major pathway for reduced susceptibility to BXA, with 30- to 50-fold and 7-fold EC50changes in A and B viruses, respectively. The viruses harboring the I38T substitution show severely impaired replicative fitness in cells, and correspondingly reduced endonuclease activity in vitro.


    Kinase Assay: Oseltamivir acid was serially diluted in MES assay buffer [32.5 mmol/L MES and 4 mmol/L CaCl2 in DW (pH 6.5 adjusted with 4 N NaOH)]. To prepare NA enzyme solution, virus stocks were inactivated by 0.1% NP-40, and diluted with MES assay buffer. Ten μL of the oseltamivir acid solution and 10 μL of the NA enzyme solution were mixed and incubated at 37 °C for 30 minutes, followed by addition of 30 μL of 100 μmol/L 2′-(4-Methylumbelliferyl)-α-D-N-acetylneuraminic acid sodium salt hydrate (MUNANA; Sigma-Aldrich Co., Ltd.). The reaction mixtures were incubated at 37 °C for 60 minutes, and the reaction was stopped by addition of 150 μL of stop solution [0.1 mol/L glycine and 25% ethanol (pH 10.7 adjusted with 4 N NaOH)]. The fluorescence intensity was measured with a microplate reader EnVision 2103 (PerkinElmer Inc.) at excitation wavelength of 355 nm and an emission wavelength of 460 nm, followed by calculation of IC50 values with XLfit software. FC was calculated by dividing IC50 of each tested virus to IC50 of the cognate wild-type virus.


    Cell Assay: Canine kidney MDCK cells were obtained from European Collection of Cell Cultures. Human quasi-diploid tumor RPMI2650 and human embryonic kidney 293 T cells were provided by American Type Culture Collection. MDCK and RPMI2650 cells were maintained in minimal essential medium (MEM)  supplemented with 10% fetal bovine serum (FBS)  and 100 µg/mL kanamycin (Thermo Fisher Scientific, Inc.). 293 T cells were cultured in Dulbecco’s modified Eagle’s medium with 10% FBS and 100 µg/mL kanamycin. Eight plasmids-based reverse genetics technique was employed to generate recombinant viruses as described. The plasmid set of rgA/WSN/33 (H1N1) and empty vector pHW2000 were provided by Dr. Robert Webster at St. Jude Children’s Research Hospital. The plasmids for the generation of rgA/Victoria/3/75 and rgB/Maryland viruses were constructed with the pHW2000 by standard molecular biology techniques. The primer sequences used are available upon request. Co-culture of MDCK and 293 T cells were transfected with the eight plasmids and incubated 48 to 72 hours, followed by propagation of the viruses in MDCK cells. The PA sequences of the recombinant viruses were verified by Sanger sequencing. Viral titers were determined by standard tissue culture infectious dose (TCID)50 assay or plaque-forming unit (PFU) assay in MDCK cells.

    In VivoIn clinical trials, single doses of Baloxavir profoundly decrease viral titers as well as alleviating influenza symptoms.  
    Animal modelN/A
    Formulation & DosageN/A
    References  2018 Jun 25;8(1):9633. 


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    Baloxavir


    In vitro endonuclease activity and inhibition of PA variants and thermal stabilization induced by the binding of BXA.  2018 Jun 25;8(1):9633.

     Baloxavir


    BXA binding to influenza A/H1N1 PA endonuclease. BXA interacts with (A) PA-A WT and (B) PA-A I38T by chelating the two manganese ions in the active site.  2018 Jun 25;8(1):9633.

     Baloxavir


    Comparison of PA endonuclease from Flu A and Flu B bound to BXA in either WT or I38T form. Superposition of PA-BXA complexes: (A) PA-A WT and PA-A I38T, (B) PA-B WT and PA-B I38T, (C) PA-A WT and PA-B WT, (D) PA-A I38T and PA-B I38T.  2018 Jun 25;8(1):9633.

     Baloxavir


    BXA binding to influenza B/Memphis PA endonuclease As Fig. 4, but for (A) PA-B WT and (B) PA-B I38T.  2018 Jun 25;8(1):9633.

     Baloxavir


    Local interactions of residue 38 in apo- and BXA-bound FluB PA (A) Superposition of ligand-free PA-B WT (PDB:5FML, in hotpink) and bound to BXA (green sticks for BXA, teal sticks/cartoon for PA). (B) Superposition of ligand-free (forest green) and BXA-bound PA-B I38T (light magenta sticks for BXA, orange sticks/cartoon for PA). 2018 Jun 25;8(1):9633.

     Baloxavir


    Replicative capacity of variant viruses with indicated AA substitutions in PA protein. Canine MDCK cells (A–C) or human RPMI2650 cells (D,E) were infected with WT or I38x viruses based on rgA/WSN/33 (H1N1) (A,D), rgA/Victoria/3/75 (H3N2) (B,E), or B/Maryland/1/5


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