2013年9月22日讯 /生物谷BIOON/--在国家自然基金与教育部人才基金资助下，中国农业大学王晓佳博士课题组突破对单一病毒的常规性研究思路，展开几种重要囊膜病毒入侵机制研究，在此基础上创造性地设计出体外体内均可高效抑制3科类病毒感染与混合感染的新型多肽。
具体设计思路如下：根据副粘病毒科新城疫病毒F糖蛋白HR2 区域、冠状病毒科传染性支气管炎病毒S糖蛋白HR2 区域，以及疱疹病毒科马立克氏病毒gH糖蛋白HR1 区域的固有特征（富含α-螺旋的结构域），将其各结构位点进行功能性突变或重组整合--即a位点高度保守（固定为亮氨酸L 或异亮氨酸I）；非重要螺旋形成单位交叉臵换为赖氨酸（K）或谷氨酸（E）（b, c, f 及g 位氨基酸，亲水位点）以促进螺旋结构间盐桥的形成；设计的新型多肽重点考虑不同病毒HR 区域在d, e 位点氨基酸（蛋白结合位点）的性质（如疏水性及极性等）进行重组设计，这不同于基因的简单叠加或者串联！课题组继而采用多种策略对多肽进行修饰，以延长其体内半衰期，最终发现无细胞毒性的胆固醇修饰多肽在病毒感染前2天或感染后1天内，每3天注射1次，一共注射4次，即可使50-70%的动物耐过高滴度病毒感染，该多肽及其修饰物的作用机理已获解析。申请3项国家发明专利，论文已于近日发表在病毒学国际权威期刊Journal of Virology（2013, 87: 9223-32）。
本系列研究突破了抗病毒制剂单一性的瓶颈，使开发广谱抗病毒多肽类阻遏剂成为可能；修饰多肽也不再需要每日注射，这为多肽类制剂的实际应用提供了重要的理论保障，推进了新型广谱抗病毒多肽类制剂的研制进程。（生物谷Bioon.com）
生物谷推荐英文摘要：
Journal of Virology doi:10.1128/JVI.01153-13
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
Chuan-Gen Li , Wang Tang, Xiao-Jing Chi , Zhi-Ming Dong , Xi-Xi Wang , Xiao-Jia Wang
In previous work, we designed peptides that showed potent inhibition of Newcastle disease virus (NDV) and infectious bronchi-tis virus (IBV) infections in chicken embryos. In this study, we demonstrate that peptides modified with cholesterol or3U of polyethylene glycol (PEG3) conjugated to the peptides’ N termini showed even more promising antiviral activities when tested in animal models. Both cholesterol- and cholesterol-PEG3-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 pep-tides 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 inocula-tion 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 pep-tide’s insertion into the host cell and thereby target an earlier stage of fusion glycoprotein activation. Our findings are of impor-tance for the further development of antivirals with broad-spectrum protective effects.
