School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
Laboratório de Virologia Comparada e Ambiental, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro 21040-900, Brazil.
Viruses. 2019 May 30;11(6):496. doi: 10.3390/v11060496.
The widespread nature of calicivirus infections globally has a substantial impact on the health and well-being of humans and animals alike. Currently, the only vaccines approved against caliciviruses are for feline and rabbit-specific members of this group, and thus there is a growing effort towards the development of broad-spectrum antivirals for calicivirus infections. In this study, we evaluated the antiviral activity of the adenosine analogue NITD008 using three calicivirus model systems namely; feline calicivirus (FCV), murine norovirus (MNV), and the human norovirus replicon. We show that the nucleoside analogue (NA), NITD008, has limited toxicity and inhibits calicivirus replication in all three model systems with EC values of 0.94 μM, 0.91 µM, and 0.21 µM for MNV, FCV, and the Norwalk replicon, respectively. NITD008 has a similar level of potency to the most well-studied NA 2'--methylcytidine . Significantly, we also show that continual NITD008 treatment effectively cleared the Norwalk replicon from cells and treatment with 5 µM NITD008 was sufficient to completely prevent rebound. Given the potency displayed by NITD008 against several caliciviruses, we propose that this compound should be interrogated further to assess its effectiveness . In summary, we have added a potent NA to the current suite of antiviral compounds and provide a NA scaffold that could be further modified for therapeutic use against calicivirus infections.
全球范围内杯状病毒感染的广泛流行对人类和动物的健康和福祉都有着重大的影响。目前，唯一获得批准的针对杯状病毒的疫苗是针对该病毒组中特定的猫和兔成员的疫苗，因此，人们正在努力开发针对杯状病毒感染的广谱抗病毒药物。在这项研究中，我们使用三种杯状病毒模型系统，即猫杯状病毒（FCV）、鼠诺如病毒（MNV）和人诺如病毒复制子，评估了腺嘌呤类似物 NITD008 的抗病毒活性。我们表明，核苷类似物（NA）NITD008 具有有限的毒性，并能抑制三种模型系统中的杯状病毒复制，其对 MNV、FCV 和诺如病毒复制子的 EC 值分别为 0.94 μM、0.91 µM 和 0.21 µM。NITD008 的效力与研究最充分的 NA 2'-甲基胞苷相当。值得注意的是，我们还表明，持续的 NITD008 治疗能有效地从细胞中清除诺如病毒复制子，5 µM 的 NITD008 治疗足以完全阻止反弹。鉴于 NITD008 对几种杯状病毒的强大活性，我们建议进一步研究该化合物，以评估其有效性。总之，我们在现有的抗病毒化合物中添加了一种有效的 NA，并提供了一种可以进一步修饰以用于治疗杯状病毒感染的 NA 支架。
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