645. S-033447/S-033188, a Novel Small Molecule Inhibitor of Cap-dependent Endonuclease of Influenza A and B Virus: In Vitro Antiviral Activity against Clinical Strains
Session: Poster Abstract Session: Oh, Those Pesky Viruses!
Thursday, October 27, 2016
Room: Poster Hall
Posters
  • IDWeek_P645_Takeshi_final.pdf (683.7 kB)
  • Background: S-033447, an active form of orally available prodrug S-033188, is a novel small molecule inhibitor of cap-dependent endonuclease (CEN) that is essential for influenza virus transcription and replication. Here, in vitro antiviral activity of S-033447 against clinically isolated influenza A and B virus in Japan from 2006 to 2014, including the neuraminidase (NA) inhibitor-resistant virus with H274Y substitution in NA (NA/H274Y), was evaluated by standard assays, such as plaque reduction and yield reduction assays in Madin-Darby canine kidney (MDCK) cells.

    Methods: In plaque reduction assay using 21 strains, cells seeded in 12-well plates were infected with virus at approximately 50 PFU/well. After 3 days incubation at 33‹C with S-033447 or favipiravir (FPV), plaque number was counted to calculate EC50. In yield reduction assay using 6 strains, cells seeded in 96-well plates were infected with virus at 100 TCID50/well. After 24 to 30 hours incubation at 37‹C with S-033447 or FPV, virus titer in the culture fluid was determined to calculate EC90.

    Results: EC50 in plaque reduction assay ranged from 0.20 to 0.99 nM for type A and from 4.01 to 11.26 nM for type B, which were typically at least three orders of magnitude lower than that of FPV. EC90 in yield reduction assay are shown in Table 1. No potency shift was observed for S-033447 against virus with NA/H274Y mutation in both assays.

    Conclusion: S-033447 exhibited broad and potent antiviral activity against clinically isolated influenza A and B virus in Japan, including viruses harboring NAI-resistance mutation.

    Table 1. EC90 of S-033447 and FPV in yield reduction assay

    EC90 (nM)

     

    S-033447

    FPV

     

    Strain

    Mean

    SD

    Mean

    SD

     

    A/Kadoma/3/2006 (H1N1)

    0.88

    0.49

    3417.76

    1810.86

     

    A/Osaka/129/2009 (H1N1)

    0.86

    0.08

    4183.69

    6.29

     

    A/Osaka/180/2009 (H1N1)a

    0.95

    0.41

    3945.39

    1216.98

     

    A/Hokkaido/12H048/2013 (H3N2)

    0.63

    0.25

    3335.60

    1102.13

     

    A/Niigata/12F392/2013 (H3N2)

    0.87

    0.52

    1898.14

    806.10

     

    B/Hokkaido/11H011/2012

    6.48

    0.97

    1735.19

    252.28

     

    B/Gunma/12G045/2013

    6.10

    0.33

    2585.87

    1825.91

     

    The mean and SD were calculated from 3 independent experiments.

    a NA/H274Y substitution

    Takeshi Noshi, MS, Atsuko Yamamoto, MS, Makoto Kawai, Ph. D., Ryu Yoshida, Ph. D., Akihiko Sato, Ph. D., Takao Shishido, Ph. D. and Akira Naito, Ph. D., SHIONOGI & CO., LTD., Toyonaka, Japan

    Disclosures:

    T. Noshi, None

    A. Yamamoto, None

    M. Kawai, None

    R. Yoshida, None

    A. Sato, None

    T. Shishido, None

    A. Naito, None

    Findings in the abstracts are embargoed until 12:01 a.m. CDT, Wednesday Oct. 26th with the exception of research findings presented at the IDWeek press conferences.