Lomonosova Elena, Daw Jil, Garimallaprabhakaran Aswin K, Agyemang Nana B, Ashani Yashkumar, Murelli Ryan P, Tavis John E
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA; Saint Louis University Liver Center, Saint Louis, MO, USA.
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA.
Antiviral Res. 2017 Aug;144:164-172. doi: 10.1016/j.antiviral.2017.06.014. Epub 2017 Jun 17.
Chronic Hepatitis B virus (HBV) infection is a major worldwide public health problem. Current direct-acting anti-HBV drugs target the HBV DNA polymerase activity, but the equally essential viral ribonuclease H (RNaseH) activity is unexploited as a drug target. Previously, we reported that α-hydroxytropolone compounds can inhibit the HBV RNaseH and block viral replication. Subsequently, we found that our biochemical RNaseH assay underreports efficacy of the α-hydroxytropolones against HBV replication. Therefore, we conducted a structure-activity analysis of 59 troponoids against HBV replication in cell culture. These studies revealed that antiviral efficacy is diminished by larger substitutions on the tropolone ring, identified key components in the substitutions needed for high efficacy, and revealed that cytotoxicity correlates with increased lipophilicity of the α-hydroxytropolones. These data provide key guidance for further optimization of the α-hydroxytropolone scaffold as novel HBV RNaseH inhibitors.
慢性乙型肝炎病毒（HBV）感染是一个全球性的重大公共卫生问题。目前的直接作用抗HBV药物靶向HBV DNA聚合酶活性，但同样重要的病毒核糖核酸酶H（RNaseH）活性尚未被开发作为药物靶点。此前，我们报道过α-羟基托酚酮化合物可抑制HBV RNaseH并阻断病毒复制。随后，我们发现我们的生化RNaseH检测低估了α-羟基托酚酮对HBV复制的疗效。因此，我们对59种托酚酮类化合物在细胞培养中针对HBV复制进行了构效关系分析。这些研究表明，托酚酮环上较大的取代基会降低抗病毒疗效，确定了高效所需取代基中的关键成分，并表明细胞毒性与α-羟基托酚酮亲脂性增加相关。这些数据为进一步优化α-羟基托酚酮支架作为新型HBV RNaseH抑制剂提供了关键指导。
