Kumar Jitendra, Singh Ankita, Tyagi Purnima, Sharma Deepti, Sarin Shiv Kumar, Kumar Vijay
Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi, 110 070 India.
Department of Chemistry, Sri Venkateswara College, University of Delhi, New Delhi, India.
Virusdisease. 2024 Dec;35(4):577-588. doi: 10.1007/s13337-024-00895-6. Epub 2024 Oct 12.
Antivirals such as nucleotide analogs (NAs) are potent inhibitors of hepatitis B virus (HBV) replication. However, NAs fail to diminish the signaling and mitogenic activities of the transactivator HBx protein. Earlier we have shown that thiourea derivative IR-415 (DSA-00) targeted HBx to down-regulate its target viral and host genes. However, the molecular mechanism of its antiviral action is poorly understood. Here we investigated the anti-HBV properties of DSA-00 and its new derivatives in cell culture models. DSA-00 and its derivatives DSA-02 and DSA-09 not only suppressed HBV DNA levels similar to well-known antiviral Entecavir but also diminished the expression of pgRNA and secretion of HBsAg and HBeAg. Apparently, the three DSA derivatives inhibited the viral pregenomic RNA expression by stabilizing the episomal DNA silencing protein SMC5, suppressed transcription from viral and host gene promoters, and normalized intracellular CDK2 activity. As none the compounds are reportedly cytotoxic, thiourea derivatives could be good candidates for developing future antivirals for a functional cure of hepatitis B infection.
The online version contains supplementary material available at 10.1007/s13337-024-00895-6.
核苷类似物（NAs）等抗病毒药物是乙型肝炎病毒（HBV）复制的有效抑制剂。然而，NAs无法降低反式激活因子HBx蛋白的信号传导和促有丝分裂活性。此前我们已表明，硫脲衍生物IR-415（DSA-00）靶向HBx以下调其靶标病毒和宿主基因。然而，其抗病毒作用的分子机制尚不清楚。在此，我们在细胞培养模型中研究了DSA-00及其新衍生物的抗HBV特性。DSA-00及其衍生物DSA-02和DSA-09不仅能像知名抗病毒药物恩替卡韦一样抑制HBV DNA水平，还能降低pgRNA的表达以及HBsAg和HBeAg的分泌。显然，这三种DSA衍生物通过稳定游离型DNA沉默蛋白SMC5来抑制病毒前基因组RNA表达，抑制病毒和宿主基因启动子的转录，并使细胞内CDK2活性恢复正常。由于据报道这些化合物均无细胞毒性，硫脲衍生物可能是开发未来用于功能性治愈乙型肝炎感染的抗病毒药物的良好候选物。
在线版本包含可在10.1007/s13337-024-00895-6获取的补充材料。
