Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, PA 18902, USA.
Antimicrob Agents Chemother. 2011 Feb;55(2):478-86. doi: 10.1128/AAC.00989-10. Epub 2010 Dec 6.
We screened ∼2,200 compounds known to be safe in people for the ability to reduce the amount of virion-associated hepatitis B virus (HBV) DNA in the culture medium of producer cells. These efforts led to the discovery of an alkylated porphyrin, chlorophyllide, as the compound that achieved the greatest reduction in signal. Here we report that chlorophyllide directly and quantitatively disrupted HBV virions at micromolar concentrations, resulting in the loss of all detectable virion DNA, without detectably affecting cell viability or intracellular viral gene products. Chemophores of chlorophyllide were also tested. Chlorin e6, a metal-free chlorophyllide-like molecule, showed the strongest antiviral activity against HBV as well as profound antiviral effects on other enveloped viruses, such as hepatitis C virus (HCV), human immunodeficiency virus (HIV), dengue virus (DENV), Marburg virus (MARV), Tacaribe virus (TCRV), and Junin viruses (JUNV). Remarkably, chlorin e6 inactivated DENV at subnanomolar-level concentrations. However, the compound had no antiviral effect against encephalomyocarditis virus and adenovirus, suggesting that chlorin e6 may be less active or inactive against nonenveloped viruses. Although other porphyrin derivatives have been previously reported to possess antiviral activity, this is the first analysis of the biochemical impact of chlorophyllide and chlorin e6 against HBV and of the dramatic anti-infectivity impact upon DENV. The possible application of this family of compounds as antiviral agents, as microbicides and systemic virus neutralizing agents, is discussed.
我们筛选了大约 2200 种已知对人体安全的化合物，以研究它们减少生产细胞培养基中病毒相关乙型肝炎病毒（HBV）DNA 的能力。这些努力发现了一种烷基化卟啉叶绿素作为能最大程度降低信号的化合物。在这里，我们报告叶绿素直接以微摩尔浓度定量破坏 HBV 病毒颗粒，导致所有可检测的病毒 DNA 丢失，而不会明显影响细胞活力或细胞内病毒基因产物。叶绿素的化学基团也进行了测试。无金属叶绿素类似物叶绿素 e6 对 HBV 表现出最强的抗病毒活性，对其他包膜病毒如丙型肝炎病毒（HCV）、人类免疫缺陷病毒（HIV）、登革热病毒（DENV）、马尔堡病毒（MARV）、Tacaribe 病毒（TCRV）和 Junin 病毒（JUNV）也有深刻的抗病毒作用。值得注意的是，叶绿素 e6 在亚纳摩尔水平的浓度下即可灭活 DENV。然而，该化合物对脑炎心肌炎病毒和腺病毒没有抗病毒作用，表明叶绿素 e6 对非包膜病毒的活性可能较低或无活性。虽然以前有报道其他卟啉衍生物具有抗病毒活性，但这是首次分析叶绿素和叶绿素 e6 对 HBV 的生化影响，以及对 DENV 的显著抗感染力的影响。讨论了这类化合物作为抗病毒剂、杀微生物剂和系统病毒中和剂的可能应用。
