Inhibitory effect of a novel thiazolidinedione derivative on hepatitis B virus entry
Inhibitory effect of a novel thiazolidinedione derivative on hepatitis B virus entry
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新型噻唑烷二酮衍生物对乙型肝炎病毒侵入的抑制作用
DOI：
10.1016/j.antiviral.2021.105165
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发表时间：
2021
影响因子：
7.6
通讯作者：
Moriishi Kohji
中科院分区：
文献类型：
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作者：
Tanaka Tomohisa;Okuyama-Dobashi Kaori;Motohashi Ryoji;Yokoe Hiromasa;Takahashi Kazunori;Wiriyasermkul Pattama;Kasai Hirotake;Yamashita Atsuya;Maekawa Shinya;Enomoto Nobuyuki;Ryo Akihide;Nagamori Shushi;Tsubuki Masayoshi;Moriishi Kohji
由于现有药物不能完全根除某些患者的慢性乙肝病毒，因此仍需要开发新的抗病毒药物来治疗乙肝病毒(HBV)感染。最近，曲格列酮和齐格列酮被归类为包括噻唑烷二酮(TZD)部分在内的化合物，它们被发现具有抑制乙肝病毒感染的作用，但这些化合物没有临床应用。在这项研究中，我们合成了11个TZD衍生物，化合物1-11，并检测了每个化合物在表达NTCP的HepG2细胞(HepG2/NTCP细胞)中对乙肝病毒感染的影响。其中化合物6的抗病毒活性最强，其IC50值为0.3kgHCVM，选择性指数(SI)为85，但化合物6不影响(Z)-5-((4‘-(naphthalen-1-yl)-[1，1′-biphenyl]-4-yl)methylene)thiazolidine-2，4-dione感染μ。化合物6可抑制原代人肝细胞(PHHs)中的乙肝病毒感染，但不能抑制HepG2.2.15细胞或HBVDNA转基因的Huh7细胞中的病毒复制。此外，复方6的治疗显著削弱了丁型肝炎病毒(HDV)的感染，并抑制了乙肝病毒颗粒内化的一步，但不抑制前S1脂肽或病毒颗粒附着到细胞表面。这些发现表明，化合物6通过抑制内化过程来干扰乙肝病毒感染。
The development of novel antivirals to treat hepatitis B virus (HBV) infection is still needed because currently available drugs do not completely eradicate chronic HBV in some patients. Recently, troglitazone and ciglitazone, classified among the compounds including the thiazolidinedione (TZD) moiety, were found to inhibit HBV infection, but these compounds are not clinically available. In this study, we synthesized 11 TZD derivatives, compounds1–11, and examined the effect of each compound on HBV infection in HepG2 cells expressing NTCP (HepG2/NTCP cells). Among the derivatives, (Z)-5-((4'-(naphthalen-1-yl)-[1,1′-biphenyl]-4-yl)methylene)thiazolidine-2,4-dione (compound6) showed the highest antiviral activity, with an IC50value of 0.3 μM and a selectivity index (SI) of 85, but compound6did not affect HCV infection. Treatment with compound6inhibited HBV infection in primary human hepatocytes (PHHs) but did not inhibit viral replication in HepG2.2.15 cells or HBV DNA-transfected Huh7 cells. Moreover, treatment with compound6significantly impaired hepatitis delta virus (HDV) infection and inhibited a step in HBV particle internalization but did not inhibit attachment of the preS1 lipopeptide or viral particles to the cell surface. These findings suggest that compound6interferes with HBV infection via inhibition of the internalization process.