Hydroxylated Tropolones Inhibit Hepatitis B Virus Replication by Blocking Viral Ribonuclease H Activity
Hydroxylated Tropolones Inhibit Hepatitis B Virus Replication by Blocking Viral Ribonuclease H Activity
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DOI：
10.1128/aac.04617-14
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发表时间：
2015-02-01
影响因子：
4.9
通讯作者：
Tavis, John E.
中科院分区：
文献类型：
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作者：
Lu, Gaofeng;Lomonosova, Elena;Tavis, John E.
尽管开发了抗病毒药物和疫苗，但乙型肝炎病毒（HBV）仍然是主要的人类病原体，部分原因是目前的治疗方法不能抑制HBV复制到足以根除病毒的程度。在这里，我们基于α -羟基曲罗酮对HIV RNaseH的活性，筛选了51种troponoid化合物，以抑制HBV RNaseH活性和HBV复制的能力，目的是确定曲罗酮药效团是否可能成为抗HBV药物开发的有前途的支架。13种化合物对HBV RNaseH有抑制作用，其中50%抑制浓度（IC50）为2.3 μ m，对HBV基因型D和C RNaseH的抑制效果相似，表明基因型特异性有限。10种化合物中有6种通过阻断病毒RNaseH活性抑制HBV复制，其中50%有效浓度（EC50）为0.34 μ M， 18种化合物抑制重组人RNaseH1，所有化合物均有中等细胞毒性（50%细胞毒性浓度[CC50] = 25 ~ 79 μ M）。治疗指标为3.8 ~ 94。有效的抑制需要一个完整的α -羟基邻苯二酮片段加上一个或多个邻苯二酮环上的短附件，但各种各样的成分是允许的。这些数据表明，如果能将毒性降到最低，类troponoids，特别是α -羟基tropolones是抗hbv药物开发的有希望的候选药物。潜在的抗rnaseh药物被设想与现有的核苷类似物联合使用，以抑制HBV复制到足以阻断基因组维持的程度，目标是根除感染。
Hepatitis B virus (HBV) remains a major human pathogen despite the development of both antiviral drugs and a vaccine, in part because the current therapies do not suppress HBV replication far enough to eradicate the virus. Here, we screened 51 troponoid compounds for their ability to suppress HBV RNaseH activity and HBV replication based on the activities of alpha-hydroxytropolones against HIV RNaseH, with the goal of determining whether the tropolone pharmacophore may be a promising scaffold for anti-HBV drug development. Thirteen compounds inhibited HBV RNaseH, with the best 50% inhibitory concentration (IC50) being 2.3 mu M. Similar inhibition patterns were observed against HBV genotype D and C RNaseHs, implying limited genotype specificity. Six of 10 compounds tested against HBV replication in culture suppressed replication via blocking of viral RNaseH activity, with the best 50% effective concentration (EC50) being 0.34 mu M. Eighteen compounds inhibited recombinant human RNaseH1, and moderate cytotoxicity was observed for all compounds (50% cytotoxic concentration [CC50] = 25 to 79 mu M). Therapeutic indexes ranged from 3.8 to 94. Efficient inhibition required an intact alpha-hydroxytropolone moiety plus one or more short appendages on the tropolone ring, but a wide variety of constituents were permissible. These data indicate that troponoids and specifically alpha-hydroxytropolones are promising lead candidates for development as anti-HBV drugs, providing that toxicity can be minimized. Potential anti-RNaseH drugs are envisioned to be employed in combination with the existing nucleos(t) ide analogs to suppress HBV replication far enough to block genomic maintenance, with the goal of eradicating infection.