2013年9月22日訊 /生物谷BIOON/--在國家自然基金與教育部人才基金資助下，中國農(nóng)業(yè)大學(xué)王曉佳博士課題組突破對單一病毒的常規(guī)性研究思路,，展開幾種重要囊膜病毒入侵機(jī)制研究,，在此基礎(chǔ)上創(chuàng)造性地設(shè)計出體外體內(nèi)均可高效抑制3科類病毒感染與混合感染的新型多肽。
具體設(shè)計思路如下：根據(jù)副粘病毒科新城疫病毒F糖蛋白HR2 區(qū)域,、冠狀病毒科傳染性支氣管炎病毒S糖蛋白HR2 區(qū)域，以及皰疹病毒科馬立克氏病毒gH糖蛋白HR1 區(qū)域的固有特征（富含α-螺旋的結(jié)構(gòu)域）,，將其各結(jié)構(gòu)位點進(jìn)行功能性突變或重組整合--即a位點高度保守（固定為亮氨酸L 或異亮氨酸I）,；非重要螺旋形成單位交叉臵換為賴氨酸（K）或谷氨酸（E）（b, c, f 及g 位氨基酸，親水位點）以促進(jìn)螺旋結(jié)構(gòu)間鹽橋的形成,；設(shè)計的新型多肽重點考慮不同病毒HR 區(qū)域在d, e 位點氨基酸（蛋白結(jié)合位點）的性質(zhì)（如疏水性及極性等）進(jìn)行重組設(shè)計,，這不同于基因的簡單疊加或者串聯(lián)！課題組繼而采用多種策略對多肽進(jìn)行修飾,，以延長其體內(nèi)半衰期,，最終發(fā)現(xiàn)無細(xì)胞毒性的膽固醇修飾多肽在病毒感染前2天或感染后1天內(nèi)，每3天注射1次,，一共注射4次,，即可使50-70%的動物耐過高滴度病毒感染，該多肽及其修飾物的作用機(jī)理已獲解析,。申請3項國家發(fā)明專利,，論文已于近日發(fā)表在病毒學(xué)國際權(quán)威期刊Journal of Virology（2013, 87: 9223-32）。
本系列研究突破了抗病毒制劑單一性的瓶頸,，使開發(fā)廣譜抗病毒多肽類阻遏劑成為可能,；修飾多肽也不再需要每日注射，這為多肽類制劑的實際應(yīng)用提供了重要的理論保障,，推進(jìn)了新型廣譜抗病毒多肽類制劑的研制進(jìn)程,。（生物谷Bioon.com）
生物谷推薦英文摘要：
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.
