|
下个病毒不知从何而来 人类迎来抗病毒新时代
2009年08月24日 10:32 来源：中国新闻网 (声明：刊用《中国新闻周刊》稿件务经书面授权)
与现在唯一已经得到广泛应用的抗流感病毒药物达菲相比，新一代抗病毒药物将可以治疗各类已知和未知病毒——包括艾滋病病毒——导致的疾病；如果试验成功，这将成为能与发现青霉素相比的医疗突破
文/吕静
今年冬季，H1N1流感病毒会不会变异、并在北半球大流行？
如果2009的H1N1流感在接下来的几个月内变得更加致命，人们将无能为力。现在，病毒已经有抵抗达菲的迹象，而抗病毒疫苗还存在很多未知问题。
H1N1流感远非我们唯一的威胁，正如2003年的SARS一样，新病原体会随时形成；一位流氓科学家，或是一位粗心的科学家，都可能释放出像天花一样的致命病毒。
“大自然是最厉害的恐怖主义者。” 迈克尔·高德布拉特说道，他曾是领导美国国防部高级研究规划局的生物防御项目的官员，现在主管美国马里兰州一家叫做功能遗传的生物技术公司。
他说：“如果你查看一下当今时代对人类构成最大威胁的病毒，你会发现，它们中的绝大多数在人类历史上都是从未出现过的：艾滋病病毒、SARS，还有埃博拉病毒，你不知道下一个病毒从哪里来。今天的人类不可能开发出针对未知或不可知病症的治疗方法，因为科学家不会有时间在一种新病毒出现后立即研制出疫苗。”
可是，高德布拉特和少数其他研究人员认为他们已经找到了答案。他们致力于研究一种全新的抗病毒药物，这种药具有一些看似不可能的功效，它们不仅能作用于大量现有的病毒，也能有效地抵抗那些尚未进化出来的病毒。更重要的是，病毒对这类药物很难产生耐药性。
这听起来好像难以置信，但是，这种药物的第一次临床试验已经产生了令人鼓舞的早期结果。如果这些药物中有几个有效，并能通过全面的人体实验，最终，医生将能够像治疗细菌病一样地治疗病毒病。
针对的是人类自身的蛋白
研制抗病毒药物的传统策略是“一种病毒，一种药物”，即找到一种能够通过与病毒蛋白质的部分结合来封锁病毒复制的药物。这种办法的问题正如在抗病毒药达菲上所发生的一样，任何微小突变造成的蛋白质形状改变都会致使药物失效。
早在上世纪90年代末，当高德布拉特还在为五角大楼工作时，他就开始琢磨是否存在另外一种策略，一种可以利用所有病毒关键弱点的策略。实际上，完全依赖其宿主(包括人、畜类、禽类等动物)的病毒本身比新生儿还无助，它们只能靠混入宿主的细胞之内来复制自己，这一过程会涉及数百个宿主蛋白质。
高德布拉特很想知道的是，动物身上是不是会存在某些蛋白质，它对病毒复制至关重要，但对宿主自己的生存无关紧要？如果确实存在，想办法使这些蛋白失效，应该就可以阻止病毒的复制，而不会杀死健康细胞。
在进入功能遗传公司后，高德布拉特开始将自己的想法付诸试验。试验很成功：他们鉴别出大约100种不同的人类蛋白质，这些蛋白质是流感病毒复制所必需、而人类细胞却并不赖以为生的，其中只有4种是以前就知道参与病毒复制过程的。
一个特别有希望的目标是编号为TSG101的一种蛋白质，很多病毒会占有和分解细胞，该蛋白质参与很多细胞内的材料运输。功能遗传公司已经研制出一种似乎可以封锁病毒与TSG101相互作用的小分子药物FGI-104，这种药物可以抑制细胞培养基中的多种病毒，包括丙型肝炎和艾滋病病毒。而且研究已经表明，该药物能防止小鼠感染埃博拉病毒。
此外，FGI-104似乎没有太大毒性。关键在于，病毒复制需要依靠的TSG101是人的蛋白质而不是病毒的蛋白质，所以，它并不会对一种病毒特异。到目前为止，研究人员已经鉴定出30多种依靠Tsg101的病毒，这些病毒来自广泛的病毒家族。这种抗体药物可结合所有感染了流感病毒、埃博拉病毒、疱疹病毒的测试细胞，甚至能将培养基中人类细胞的艾滋病病毒降低到可检测水平之下。
功能遗传公司计划明年申请开始这一抗体药物的临床试验许可证。
更宽泛的思路
通过随机药物筛选，该公司还确定了另一种同样具有广泛抗病毒效果的候选药物FGI - 103。
这种药物的作用原理尚不清楚，但在用小鼠所做的实验中，该药的作用非常显著。高德布拉特说：“如果在实验动物感染埃博拉病毒后的一天之内给予该药，我们能救活100%的动物。如果感染病毒后两天内给药，我们能救活80%的动物。过了4天，我们还能救活40%的动物。如若不然，在第七天的时候就会出现可怕的死亡。这种药物的治疗作用是很明显的。”
其他研究小组也正在进一步揭开病毒的弱点。比如，病毒学教科书会告诉你，假如一个试管中放有分离出来的蛋白质，病毒会自动地用这些蛋白质成分来装配其蛋白质外壳。加州大学旧金山分校的维什瓦纳特·林格帕和同事发现，病毒的组装取决于宿主的许多种蛋白的存在。
很多这类蛋白质与病毒组装看上去并没有明显的联系。比如，有一种蛋白质通常会抑制一种切割RNA的酶，林格帕解释说：“这对装配病毒衣壳有什么关系呢？病毒会进去说道：‘你，停下正在为主人所做的事情，现在为我工作。’”
林格帕意识到，这些被劫持的蛋白质可能是抗病毒治疗的一个靶标，他在旧金山创建的婆罗塞塔生物构建公司就是要将这一想法商业化。他的研究小组发现，每一个病毒家族似乎都会依赖各不相同的一套20到40个被劫持蛋白质来组装衣壳，但是一个病毒家族中的所有成员都会利用非常相似的一组蛋白质。
这意味着婆罗塞塔公司的候选药物比功能遗传公司的药物能对付的病毒种类要少。但即便如此，它们也比常规抗病毒药物达菲所覆盖的杀毒范围更广。比如，有一种化合物已经被试验证明能有效阻止细胞培养基中 6种不同的黄病毒，包括登革热、黄热病、西尼罗河热和丙型肝炎。这家公司正在开发的药物已经能够对付引起人类疾病的已知21种病毒中的14种，他们希望在今年的晚些时候开始与大型制药公司谈判合作。
林格帕发现，这些药物可以令许多宿主蛋白质失效，却不至于引起宿主的严重副作用， 他说：“可是病毒，至少在目前的研究假定下，绝对要依赖某种特定的蛋白质，如果你阻止了这种蛋白质，病毒就不走运了，但宿主细胞可以转向其他蛋白质说：‘嗨，你能过来一下吗？你能做一半的替换工作吗？’”
癌症和艾滋病都能抑制
也许最有前途的广谱抗病毒药物正在由菲利普·索普研发，此人是位于达拉斯的美国得克萨斯大学西南医学中心的研究人员。和高德布拉特一样，索普发现了病毒感染的另一种“足迹”。
在健康的细胞中，某些分子只会出现在细胞膜的内表面，这些分子包括被称之为磷脂酰丝氨酸的脂类物质，这是最常见的细胞膜组成成分之一。当细胞受到压力时，比如说感染了病毒，一些磷脂酰丝氨酸就会出现在细胞膜的外表层。
因此，正如FGI - 104抗体的靶标是暴露的TSG101蛋白，索普和同事已经设计出一种抗体bavituximab，它是抗磷脂酰丝氨酸的单克隆抗体。这种药物能与暴露的磷脂酰丝氨酸结合。一旦bavituximab与之结合，免疫系统会迅速摧毁受病毒感染的细胞，这样就限制了病毒的复制。
另外，很多普通病毒在潜伏期会将自身包裹在宿主细胞膜内。这种“膜套”可能起着隐形罩衣的作用，使得病毒得以躲过免疫系统。而bavituximab这种药能与这个罩衣结合，让病毒暴露在免疫系统之下。所以，至少在理论上，bavituximab能够在病毒感染细胞之前就引发包膜病毒的毁灭。
去年，索普小组在《自然医学》上发表研究报告，他们用bavituximab对感染了一种沙粒病毒的豚鼠做试验。结果，用bavituximab治疗的动物有一半被救活了，而对照组的动物却全数死亡。
美国加利福尼亚塔斯廷的百富勤制药公司，现在正在测试bavituximab对其他各种病毒的抗毒效果，这些病毒包括艾滋病、丙型肝炎、流行性感冒、麻疹病毒、以及天花与狂犬病毒家族。到目前为止，他们检查的每种病毒都留下了磷脂酰丝氨酸足迹。从目前结果看来，未来像bavituximab这样的药就能帮助战胜每一种已知人类病毒。
更进一步的临床试验还测试了bavituximab作为抗癌药的效果，因为磷脂酰丝氨酸也会出现在肿瘤细胞表面。所以，人们认为它们只会杀死肿瘤细胞而不会对周围健康组织造成危害。这些试验也表明，这种药物应该是安全的。
等待和争议
虽然这种概念已经为科学界所知，但宿主标靶(即把目标瞄准人体自身的特定蛋白质)的抗病毒治疗还处在早期阶段。事实上，很多专家对这一想法是持怀疑态度的。高德布拉特说：“患传染病的人对标靶病原体并不会感觉不舒服，他们不舒服的是标靶宿主。”一个原因是可能的副作用风险更高，特别是病毒感染需要长时间的治疗。
美国国家过敏症与传染病研究所负责协调生物防御研究的迈克尔·奎瑞拉说：“除非我们能把这些药物用在人体上，并通过试验，否则谈论其是否有效还为时过早。”
另一方面，宿主标靶的抗病毒药比传统抗病毒药有更多的优势。首先，它们提供了一种应对新病毒的方法。虽然它们还没有做好准备以及时帮助我们击退HINI流感，但下一次，当一种新病毒开始在人类中传播的时候，我们可能就不会像现在这样无助。或许，不出10年或20年，现在审批通过的抗病毒药都会下架。 ★
Viruses do not know where the next anti-virus from human usher in new era
At 10:32 on August 24, 2009 Source: China News Network (statement: Manuscripts, "China News Weekly" releases works by the written authorization)
And now only has been widely used anti-influenza drug Tamiflu compared to a new generation of antiviral drugs will be able to treat various types of known and unknown viruses - including HIV - caused by disease; If the trial is successful, it will as compared with the discovery of penicillin medical breakthroughs
Text / LV Jing
This winter, H1N1 influenza virus will mutate and in the northern hemisphere of a pandemic?
If 2009 of the H1N1 flu in the next few months become more lethal, people will do anything. Today, viruses have been signs of resistance to Tamiflu, while the anti-viral vaccines are still many unknown problems.
H1N1 flu is far from our only threat, as in 2003, SARS, the new pathogens will not hesitate to form; a rogue scientist, or a careless scientist, could unleash a deadly virus like smallpox.
"Nature is the most powerful terrorist." Debulate Michael Gao said he was leading the United States Defense Advanced Research Projects Agency's biological defense program officials, and now in charge of Maryland, a bio-technology called functional genetic公司.
He said: "If you look at the current era the greatest threat to mankind posed by the virus, you will find that the vast majority of them are in human history has never happened before: HIV, SARS, Ebola, there is virus, you do not know the virus come from the next one. Today's humanity can not be developed for the unknown or unknowable disease treatment, because scientists would not have time for a new virus to appear immediately after the development of vaccines. "
However, high Debulate and a few other researchers think they have found the answer. Their commitment to research a new antiviral drugs, this drug has some seemingly impossible effect, they not only can function in a large number of existing viruses, but also can effectively fight against those who have not yet evolved out of the virus. More importantly, the virus resistant to these drugs is difficult.
It sounds incredible, but that the first clinical trials of drugs has produced encouraging early results. If these drugs, there are several effective and pass the comprehensive human experiments, eventually, doctors will be able to like the same as the treatment of bacterial diseases to treat viral diseases.
Aimed at human self-proteins
Development of antiviral drugs, the traditional strategy is "a virus, a drug," that is to find a way to part with the viral protein binding of drugs to block viral replication. Problem of this approach as in the antiviral drug Tamiflu, like what happened, any small change in the shape of proteins caused by mutations will cause drug ineffective.
As early as the late 90s of the last century, when the high-Debulate still working for the Pentagon, he began pondering whether there is another strategy, a key weakness of all viruses can be used strategy. In fact, entirely dependent on its host (including human, animal, poultry and other animals) than the newborns of the virus itself also does not help, they can only rely on mixed within the host cells to replicate themselves, this process will involve hundreds of host proteins.
High Debulate really want to know is that animals not be the existence of certain proteins, it is essential viral replication, but the host's own survival does not matter? If you do exist, to find ways to make these proteins fail to be able to prevent viral replication, but not kill healthy cells.
Into the function of genetic company, high Debulate began to put to test their own ideas. Test was very successful: they identified about 100 different human proteins, these proteins are required for influenza virus replication, but they are not a living human cells, of which only 4 species were known before the process involved in viral replication.
A particularly promising goal is numbered TSG101 as a protein, a lot of possession and decomposition of the virus cells, the intracellular proteins involved in a lot of material transport. Functional Genetics has developed a virus and TSG101 seems to block the interaction of small molecule drug FGI-104, this drug can inhibit the cell culture media in a variety of viruses, including hepatitis C and HIV. And studies have shown that the drug can prevent mice infected with Ebola virus.
In addition, FGI-104 do not seem very toxic. The key is to rely on viral replication of TSG101 is a human protein rather than viral proteins, so it will not have a virus-specific. So far, researchers have identified more than 30 kinds of relying on Tsg101 virus, these viruses from a wide range of the virus family. This antibody-based drugs can be combined for all infected with the influenza virus, Ebola virus, herpes virus test cells, and even human cells in culture medium can of HIV can be reduced to below the detection level.
Functional Genetics company plans to apply next year to begin this antibody drugs in clinical trials permit.
Broader idea
Through random drug screening, the company also identified another equally wide range of anti-viral effect of drug candidates FGI - 103.
The role of the principle of this drug is not yet clear, but in experiments done with mice, the drug's role is very significant. High Debulate said: "If in experimental animals infected with Ebola virus, one day after giving the drug, we can save 100% of the animals. If administered within two days after infection, we can save 80% animals. After a 4-day, we can save 40% of the animals. Otherwise, in the seventh day when there will be terrible death. The therapeutic effect of this drug is very clear. "
Other research groups are also being further reveal weaknesses in the virus. For example, virology textbook will tell you that if a test tube placed in separate proteins, the virus will automatically use these protein components to assemble their protein shell. University of California at San Francisco's Weishenwana Thelin Gepa and colleagues found that the virus assembly depends on the host of many kinds of proteins exist.
Many of these proteins and virus assembly appears to be no obvious links. For example, there is a protein that normally prevent a cut RNA, enzymes, Linge Pa explained: "This assembly of the virus capsid, what relationship? Virus will go, said: 'you, stop being the main person doing , and now works for me '. "
Linge Pa aware that these proteins may be hijacked antiviral therapy a target, he created in San Francisco Po Rosetta is a biotechnology company to the idea of building a commercial. His research team found that each one of the family seems to have to rely on different set of 20-40 have been hijacked to assemble capsid proteins, but a virus, all members of the family will be very similar to the use of a group of proteins.
This means that po Rosetta's drug candidate than the functional Genetics of drugs could be less kind to deal with the virus. But even so, they are compared to conventional antiviral drugs, Tamiflu covered by the broader anti-virus. For example, there is a test compound has been shown to effectively prevent the cell culture medium in 6 different yellow viruses, including dengue fever, yellow fever, West Nile fever and hepatitis. The company is developing the drug has been able to deal with the known human diseases caused by 21 of the 14 kinds of viruses, they hope to begin later this year, negotiations on cooperation with large pharmaceutical companies.
Linge Pa found that these drugs can make a number of host proteins failure, but the host Buzhi Yu cause serious side effects, he said: "But the virus, at least under the assumption that the current study is absolutely dependent on a particular protein, if you stop of this protein, the virus is not luck, but the host cells could be turned to other proteins, said: 'Hey, can you come here? You can do half of the replacement work?' "
Could inhibit cancer and AIDS
Perhaps the most promising broad-spectrum antiviral drugs are being developed by the菲利普索普, this person is located in Dallas Texas Southwestern Medical Center researchers. And high-Debulate like Thorpe found that a virus infection in another "footprint."
In healthy cells, some elements will appear in the inner cell membrane surface, these molecules including those known as lipid phosphatidylserine, which is the most common components of cell membranes. When cells are stressed, such as a virus, a number of phosphatidylserine will appear on the outer surface of the cell membrane.
Thus, as FGI - 104 antibodies target is exposed TSG101 protein, Thorpe and his colleagues have designed an antibody bavituximab, it is the anti-phosphatidylserine monoclonal antibodies. This drug with the exposed phosphatidylserine binding. Once the bavituximab combined with the immune system will quickly destroy the infected cells, thus limiting viral replication.
In addition, many common virus in the incubation period will be wrapped itself in the host cell membrane. This "film set" may play a hidden role in gowns, making the virus to escape the immune system. The bavituximab this drug combination with the gowns, so that the immune system under exposure to the virus. So, at least in theory, bavituximab virus-infected cells can be triggered prior to the destruction of the virus envelope.
Last year, Thorpe Panel in the "Nature Medicine," published research reports, they used a sand bavituximab virus infected guinea pig test. Results, the bavituximab half of treated animals were saved, while the control group animals are all dead.
Tustin, California Peregrine Pharmaceuticals Inc., is now being tested on a variety of other viruses bavituximab anti-drug effects, these viruses, including AIDS, hepatitis C, influenza, measles virus, and smallpox and rabies virus family. So far, they checked each virus have left footprints of phosphatidylserine. From the current results, future drugs such as bavituximab can help to overcome each and a known human viruses.
Further clinical trials also tested the effect of bavituximab as an anti-cancer drugs, as phosphatidyl serine also appear on the surface of tumor cells. Therefore, people think that they would kill only tumor cells but not harm the surrounding healthy tissue. These tests also show that this drug should be safe.
Wait and controversy
Although this concept has been known for the scientific community, but the target host (that is targeting the body's own specific protein) and anti-viral therapy is still in an early stage. In fact, many experts on this idea was skeptical. High Debulate said: "The risk of infectious disease pathogens and target people will not feel uncomfortable, they are not comfortable with the target host." One reason is a higher risk of possible side effects, in particular, is a viral infection requires long - the time of treatment.
U.S. National Institute of Allergy and Infectious Diseases is responsible for coordinating Michael Kuirui La biological defense research, said: "Unless we can use these drugs in humans, and through testing, or too early to talk about their validity."
On the other hand, target of antiviral host anti-viral drugs have more than a traditional advantages. First, they provide a way to respond to new viruses. Although they were not ready in time to help us defeat HINI influenza, but next time, when a new virus began to spread in humans, we may not be as they are now helpless. Perhaps less than 10 years or 20 years, and now adopted by the anti-viral drugs will be approved under the aircraft. ★
|
