新聞中心
緊跟行業(yè)步伐，共享前沿資訊
industry
news
行業(yè)新聞
HCV感染中p7蛋白結(jié)構(gòu)及與藥物作用機(jī)理解析
2019-08-18 09:23
國際權(quán)威學(xué)術(shù)期刊《自然》在線發(fā)表了美國哈佛大學(xué)醫(yī)學(xué)院、中科院上海生化與細(xì)胞所/國家蛋白質(zhì)科學(xué)中心•上海（籌）周界文研究員所帶領(lǐng)課題組的最新 成果，首次解析了丙型肝炎病毒（hepatitis C virus）感染宿主過程中重要離子通道蛋白p7的精細(xì)空間結(jié)構(gòu)以及p7與抑制劑金剛烷胺類藥物相互作用的分子機(jī)理。
丙型肝炎病毒（HCV）與艾滋病病毒（HIV）、流感病毒（influenza virus)一樣，屬于危害性強(qiáng)的RNA病毒。丙型肝炎病毒所引起的病毒性肝炎，是慢性肝炎的主要病原之一，嚴(yán)重時(shí)會(huì)導(dǎo)致肝硬化和肝癌。目前估計(jì)全世界有 1億7千萬人感染HCV，我國的HCV攜帶者和患者總數(shù)均居世界首位，屬于丙肝高發(fā)區(qū)，迄今為止還沒有研發(fā)出有效控制HCV的預(yù)防或治療性疫苗。
長期以來，對(duì)病人使用的標(biāo)準(zhǔn)治療方法是持續(xù)混合使用長效干擾素(peginterferon-?)和利巴韋林(ribavirin)。但這種治 療方法療效有限、周期長、費(fèi)用昂貴，并常伴有毒副作用。最近以標(biāo)準(zhǔn)療法聯(lián)用新上市的NS3/4A抑制劑Telaprevir和Boceprevir等，雖 然可以提高治療效果，但抗藥性突變病毒的產(chǎn)生一直是一個(gè)潛在的問題。目前國際上抗RNA病毒治療的發(fā)展方向是建立一種基于多種藥物靶點(diǎn)的聯(lián)合療法，因此迫 切需要開發(fā)多個(gè)作用靶點(diǎn)，尋找更有效的治療方法和干預(yù)手段。
p7是HCV基因表達(dá)的唯一的離子通道蛋白，對(duì)病毒顆粒的組裝和成熟、病毒顆粒的釋放必不可少，突變和完全刪除p7會(huì)導(dǎo)致HCV病毒不能產(chǎn)生感 染性。離子通道蛋白是一類在許多病毒中廣泛存在的蛋白質(zhì)，對(duì)于病毒的生活周期產(chǎn)生重要影響，被廣泛作為潛在藥物靶點(diǎn)加以研究，例如流感病毒的M2蛋白和艾 滋病病毒的Vpu蛋白。但是以p7為靶點(diǎn)的抗HCV藥物研究卻進(jìn)展緩慢，主要原因是由于p7是一個(gè)跨膜蛋白，形成多聚體陽離子通道后，結(jié)構(gòu)復(fù)雜、構(gòu)象靈 活，給結(jié)構(gòu)研究、尤其是蛋白質(zhì)結(jié)晶帶來極大困難，因此，長期以來缺乏p7離子通道的三維結(jié)構(gòu)及其與小分子化合物結(jié)合的作用機(jī)理。
在無法得到蛋白質(zhì)晶體的情況下，周界文研究員和歐陽波博士（文章第一作者）建立了一種基于核磁共振的方法，最終解析了此病毒通道的結(jié)構(gòu)。此通道 結(jié)構(gòu)非常特異，形成花瓣形的六聚體結(jié)構(gòu)，是目前使用核磁共振技術(shù)解析出的最大的離子通道結(jié)構(gòu)。由結(jié)構(gòu)帶來的啟發(fā)，周界文課題組與上海巴斯德所、中科院上海 生化細(xì)胞所孫兵課題組合作，首次鑒定了金剛烷胺類化合物對(duì)p7的離子通道活性發(fā)揮抑制作用的結(jié)合位點(diǎn)，并通過一系列的功能測試，揭示了p7通道離子轉(zhuǎn)運(yùn)和 藥物抑制的機(jī)理。
通過對(duì)這些病毒離子通道結(jié)構(gòu)和機(jī)制方面的理解，科學(xué)家期望在不久的將來可以研制出新一代抗丙型肝炎病毒的治療手段。
The international authoritative academic journal "Nature" published online the latest results of the research team led by the Shanghai Institute of Biochemistry and Cytology / National Center for Protein Sciences of the Harvard University Medical School and the Chinese Academy of Sciences. For the first time, the fine spatial structure of important Ionic channel protein P7 and the molecular mechanism of interaction between P7 and the inhibitor Jingangwane were analyzed during the infection of the hepatitis C virus(hepatitis C virus).
Hepatitis C virus(HCV), like HIV and influenza virus, is a highly harmful RNA virus. Viral hepatitis caused by the hepatitis C virus is one of the main pathogens of chronic hepatitis and can cause cirrhosis and liver cancer in severe cases. At present, it is estimated that 170 million people in the world are infected with HCV. The total number of HCV carriers and patients in China ranks first in the world and belongs to the high incidence area of HCV. To date, no preventive or therapeutic vaccine has been developed to effectively control HCV.
For a long time, the standard treatment for patients has been the continued use of a combination of long-acting interferon(peginterferon-<UNK>) and ribavirin. However, this therapeutic method has limited efficacy, long cycle, high cost, and often toxic side effects. Recently, the newly listed NS3/4A inhibitors Telaprevir and Boceprevir, etc., have been used in combination with standard therapies. Although treatment effectiveness can be improved, the generation of drug-resistant mutants has been a potential problem. At present, the development direction of anti-RNA virus treatment in the world is to establish a combination therapy based on multiple drug targets. Therefore, it is imperative to develop multiple target targets and find more effective treatment methods and interventions.
P7 is the only ion channel protein expressed by HCV gene. It is indispensable for the assembly and maturity of virus particles and the release of virus particles. Mutations and the complete deletion of P7 will cause HCV viruses to fail to produce susceptibility. Ion channel protein is a type of protein that is widely present in many viruses and has an important impact on the life cycle of the virus. It has been widely studied as a potential drug target, such as M2 protein of influenza virus and Vpu protein of AIDS virus. However, the research on anti-HCV drugs targeting P7 has progressed slowly. The main reason is that P7 is a transmembrane protein. After forming a polymer cation channel, the structure is complex and the structure is active, which brings great difficulties to structural research, especially protein crystallization. Therefore, the three-dimensional structure of the P7 ion channel and its mechanism of binding to small molecular compounds have long been lacking.
In the absence of protein crystals, Zhou Jiwen's researcher and Dr. Ouyangbo(the first author of the article) established a method based on nuclear magnetic resonance that eventually resolved the structure of the virus channel. This channel structure is very specific, forming a petal-shaped hexamer structure, which is currently the largest ion channel structure resolved using nuclear magnetic resonance technology. Inspired by the structure, the Zhoujiewen Group cooperated with the Shanghai Pasteur Institute and the Shanghai Biochemical Cell Institute of the Chinese Academy of Sciences, Sunbing Jingangwane, to identify for the first time the binding site for the inhibition of the ion channel activity of the P7 by the Jingangwane compound. And through a series of functional tests, The mechanism of ion transport and drug inhibition in P7 channel was revealed.
Through the understanding of the structure and mechanism of these virus ion channels, scientists expect to develop a new generation of treatments for hepatitis C virus in the near future.
The international authoritative academic journal "Nature" published online the latest results of the research team led by the Shanghai Institute of Biochemistry and Cytology / National Center for Protein Sciences of the Harvard University Medical School and the Chinese Academy of Sciences. For the first time, the fine spatial structure of important Ionic channel protein P7 and the molecular mechanism of interaction between P7 and the inhibitor Jingangwane were analyzed during the infection of the hepatitis C virus(hepatitis C virus).
Hepatitis C virus(HCV), like HIV and influenza virus, is a highly harmful RNA virus. Viral hepatitis caused by the hepatitis C virus is one of the main pathogens of chronic hepatitis and can cause cirrhosis and liver cancer in severe cases. At present, it is estimated that 170 million people in the world are infected with HCV. The total number of HCV carriers and patients in China ranks first in the world and belongs to the high incidence area of HCV. To date, no preventive or therapeutic vaccine has been developed to effectively control HCV.
For a long time, the standard treatment for patients has been the continued use of a combination of long-acting interferon(peginterferon-<UNK>) and ribavirin. However, this therapeutic method has limited efficacy, long cycle, high cost, and often toxic side effects. Recently, the newly listed NS3/4A inhibitors Telaprevir and Boceprevir, etc., have been used in combination with standard therapies. Although treatment effectiveness can be improved, the generation of drug-resistant mutants has been a potential problem. At present, the development direction of anti-RNA virus treatment in the world is to establish a combination therapy based on multiple drug targets. Therefore, it is imperative to develop multiple target targets and find more effective treatment methods and interventions.
P7 is the only ion channel protein expressed by HCV gene. It is indispensable for the assembly and maturity of virus particles and the release of virus particles. Mutations and the complete deletion of P7 will cause HCV viruses to fail to produce susceptibility. Ion channel protein is a type of protein that is widely present in many viruses and has an important impact on the life cycle of the virus. It has been widely studied as a potential drug target, such as M2 protein of influenza virus and Vpu protein of AIDS virus. However, the research on anti-HCV drugs targeting P7 has progressed slowly. The main reason is that P7 is a transmembrane protein. After forming a polymer cation channel, the structure is complex and the structure is active, which brings great difficulties to structural research, especially protein crystallization. Therefore, the three-dimensional structure of the P7 ion channel and its mechanism of binding to small molecular compounds have long been lacking.
In the absence of protein crystals, Zhou Jiwen's researcher and Dr. Ouyangbo(the first author of the article) established a method based on nuclear magnetic resonance that eventually resolved the structure of the virus channel. This channel structure is very specific, forming a petal-shaped hexamer structure, which is currently the largest ion channel structure resolved using nuclear magnetic resonance technology. Inspired by the structure, the Zhoujiewen Group cooperated with the Shanghai Pasteur Institute and the Shanghai Biochemical Cell Institute of the Chinese Academy of Sciences, Sunbing Jingangwane, to identify for the first time the binding site for the inhibition of the ion channel activity of the P7 by the Jingangwane compound. And through a series of functional tests, The mechanism of ion transport and drug inhibition in P7 channel was revealed.
Through the understanding of the structure and mechanism of these virus ion channels, scientists expect to develop a new generation of treatments for hepatitis C virus in the near future.
上一篇：
HIV感染的臨床分期
下一篇：
艾滋病的臨床表現(xiàn)