Optimization and Synthesis of Pyridazinone Derivatives as Novel Inhibitors of Hepatitis B Virus by Inducing Genome-free Capsid Formation
Optimization and Synthesis of Pyridazinone Derivatives as Novel Inhibitors of Hepatitis B Virus by Inducing Genome-free Capsid Formation
复制标题
通过诱导无基因组衣壳形成优化和合成哒嗪酮衍生物作为乙型肝炎病毒新型抑制剂
DOI：
10.1021/acsinfecdis.6b00159
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发表时间：
2017-03-01
影响因子：
5.3
通讯作者：
Hu, Youhong
中科院分区：
文献类型：
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作者：
Lu, Dong;Liu, Feifei;Hu, Youhong
B型肝炎病毒（HBV）衣壳蛋白在病毒DNA复制中起着重要作用。靶向核衣壳功能已被证明是抗HBV药物开发的有效方法。高通量筛选和机制研究揭示了命中化合物4a作为HBV装配效应物（AEf），其可以通过诱导形成HBV DNA游离衣壳来抑制HBV复制。随后的SAR研究和药物样优化导致发现了先导候选物4 r，其具有有效的抗病毒活性（IC 50 = 0.087 +/- 0.002 μ M）、低细胞毒性（CC 50 = 90.6 +/- 2.06 μ M）、对核苷类似物抗性HBV突变体的敏感性以及与核苷类似物在HepG2.2.15细胞中的协同效应。
The capsid of hepatitis B virus (HBV) plays a vital role in virus DNA replication. Targeting nucleocapsid function has been demonstrated as an effective approach for anti-HBV drug development. A high-throughput screening and mechanism study revealed the hit compound 4a as an HBV assembly effector (AEf), which could inhibit HBV replication by inducing the formation of HBV DNA-free capsids. The subsequent SAR study and drug-like optimization resulted in the discovery of the lead candidate 4r, with potent antiviral activity (IC50 = 0.087 +/- 0.002 mu M), low cytotoxicity (CC50 = 90.6 +/- 2.06 mu M), sensitivity to nucleoside analogue -resistant HBV mutants, and synergistic effect with nucleoside analogues in HepG2.2.15 cells.