A Cholesterol Tag at the N Terminus of the Relatively Broad-Spectrum Fusion Inhibitory Peptide Targets an Earlier Stage of Fusion Glycoprotein Activation and Increases the Peptide's Antiviral Potency In Vivo
A Cholesterol Tag at the N Terminus of the Relatively Broad-Spectrum Fusion Inhibitory Peptide Targets an Earlier Stage of Fusion Glycoprotein Activation and Increases the Peptide's Antiviral Potency In Vivo
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DOI：
10.1128/jvi.01153-13
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发表时间：
2013-08-01
影响因子：
5.4
通讯作者：
Wang, Xiao-Jia
中科院分区：
文献类型：
--
作者：
Li, Chuan-Gen;Tang, Wang;Wang, Xiao-Jia
在之前的工作中，我们设计的多肽对鸡胚胎中的新城疫病毒(NDV)和传染性支气管炎病毒(IBV)感染具有很强的抑制作用。在这项研究中，我们证明了用胆固醇或3U聚乙二醇(PEG3)修饰的多肽与多肽的N端结合在一起，在动物模型中显示出更有希望的抗病毒活性。胆固醇和胆固醇聚乙二醇3标记的多肽均能保护鸡胚免受不同血清型新城疫病毒和新城疫病毒的感染。相比之下，未标记的多肽需要在接近病毒接种时间时进行干预，以实现类似水平的保护。病毒感染前1天肌肉注射胆固醇多肽1.6 mg/kg，病毒接种后间隔3天肌肉注射3次，保护70%的雏鸡免受新城疫病毒感染。我们进一步证明，胆固醇标记的多肽在体内的半衰期比未标记的多肽要大。它还有可能穿过血脑屏障进入鸟类的中枢神经系统(CNS)。最后，我们证明了胆固醇标记的多肽可以在病毒融合多肽插入宿主细胞之前发挥作用，从而靶向融合糖蛋白激活的早期阶段。我们的发现对进一步开发具有广谱保护作用的抗病毒药物具有重要意义。
In previous work, we designed peptides that showed potent inhibition of Newcastle disease virus (NDV) and infectious bronchitis virus (IBV) infections in chicken embryos. In this study, we demonstrate that peptides modified with cholesterol or 3 U of polyethylene glycol (PEG(3)) conjugated to the peptides' N termini showed even more promising antiviral activities when tested in animal models. Both cholesterol- and cholesterol-PEG(3)-tagged peptides were able to protect chicken embryos from infection with different serotypes of NDV and IBV when administered 12 h prior to virus inoculation. In comparison, the untagged peptides required intervention closer to the time of viral inoculation to achieve a similar level of protection. Intramuscular injection of cholesterol- tagged peptide at 1.6 mg/kg 1 day before virus infection and then three times at 3-day intervals after viral inoculation protected 70% of the chickens from NDV infection. We further demonstrate that the cholesterol- tagged peptide has an in vivo half-life greater than that of untagged peptides. It also has the potential to cross the blood-brain barrier to enter the avian central nervous system (CNS). Finally, we show that the cholesterol- tagged peptide could play a role before the viral fusion peptide's insertion into the host cell and thereby target an earlier stage of fusion glycoprotein activation. Our findings are of importance for the further development of antivirals with broad-spectrum protective effects.