TY - JOUR
T1 - Identification of KX2-391 as an inhibitor of HBV transcription by a recombinant HBV-based screening assay
AU - Harada, Keisuke
AU - Nishitsuji, Hironori
AU - Ujino, Saneyuki
AU - Shimotohno, Kunitada
N1 - Funding Information:
We thank Ms. Hiromi Yamamoto, Ritsuko Shiina and Atsuno Kaneto for technical assistance. This work was partly supported by Grants-in-Aid for Scientific Research from the Ministry of Health, Labor, and Welfare of Japan (H24-006) and by Grants-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (22114004) and Grants-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (15K19121) and by the Research Program on Hepatitis from Japan Agency for Medical Research and Development, AMED (17fk0310104h0001).
Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2017/8
Y1 - 2017/8
N2 - Antiviral therapies for chronic hepatitis B virus (HBV) infection that are currently applicable for clinical use are limited to nucleos(t)ide analogs targeting HBV polymerase activity and pegylated interferon alpha (PEG-IFN). Towards establishing an effective therapy for HBV related diseases, it is important to develop a new anti-HBV agent that suppresses and eradicates HBV. This study used recombinant HBV encoding NanoLuc to screen anti-HBV compounds from 1827 US Food and Drug Administration approved compounds and identified several compounds that suppressed HBV infection. Among them, KX2-391, a non-ATP-competitive inhibitor of SRC kinase and tubulin polymerization, was identified as a lead candidate for an anti-HBV drug. Treatment of sodium taurocholate cotransporting polypeptide (NTCP) transduced-HepG2 (HepG2-NTCP) or primary human hepatocytes with KX2-391 suppressed HBV replication in a dose-dependent manner. The anti-HBV activity of KX2-391 appeared not to depend on SRC kinase activity because siRNA for SRC mRNA did not impair the HBV infection/replication. The anti-HBV activity of KX2-391 depended on the inhibitory effect of tubulin polymerization similar to other tubulin polymerization inhibitors, some of which were shown to inhibit HBV replication. KX2-391 inhibited HBV transcription driven by a HBV precore promoter in an HBV X protein-independent manner but did not inhibit the activity of HBV-S1, -S2, -X or cytomegalovirus promoters. Treatment with KX2-391 reduced the expression of several various factors including hepatocyte nuclear factor-4a.
AB - Antiviral therapies for chronic hepatitis B virus (HBV) infection that are currently applicable for clinical use are limited to nucleos(t)ide analogs targeting HBV polymerase activity and pegylated interferon alpha (PEG-IFN). Towards establishing an effective therapy for HBV related diseases, it is important to develop a new anti-HBV agent that suppresses and eradicates HBV. This study used recombinant HBV encoding NanoLuc to screen anti-HBV compounds from 1827 US Food and Drug Administration approved compounds and identified several compounds that suppressed HBV infection. Among them, KX2-391, a non-ATP-competitive inhibitor of SRC kinase and tubulin polymerization, was identified as a lead candidate for an anti-HBV drug. Treatment of sodium taurocholate cotransporting polypeptide (NTCP) transduced-HepG2 (HepG2-NTCP) or primary human hepatocytes with KX2-391 suppressed HBV replication in a dose-dependent manner. The anti-HBV activity of KX2-391 appeared not to depend on SRC kinase activity because siRNA for SRC mRNA did not impair the HBV infection/replication. The anti-HBV activity of KX2-391 depended on the inhibitory effect of tubulin polymerization similar to other tubulin polymerization inhibitors, some of which were shown to inhibit HBV replication. KX2-391 inhibited HBV transcription driven by a HBV precore promoter in an HBV X protein-independent manner but did not inhibit the activity of HBV-S1, -S2, -X or cytomegalovirus promoters. Treatment with KX2-391 reduced the expression of several various factors including hepatocyte nuclear factor-4a.
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U2 - 10.1016/j.antiviral.2017.06.005
DO - 10.1016/j.antiviral.2017.06.005
M3 - Article
C2 - 28624460
AN - SCOPUS:85020922330
VL - 144
SP - 138
EP - 146
JO - Antiviral Research
JF - Antiviral Research
SN - 0166-3542
ER -