【齐心抗疫】《科学现场》：专家如何应对新冠病毒

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How experts plan to treat the new coronavirus | Live Science
专家如何应对新冠病毒 |《科学现场》

06 February 2020
2020年02月06日
By Yasemin Saplakoglu
文 | 亚塞明·沙普拉克奥卢

                               
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As the coronavirus outbreak in China continues to spread, having infected over 24,000 people so far, scientists around the world are racing to find a treatment. Most of the people infected with the new coronavirus, dubbed 2019-nCov, have not received a treatment specific to that virus — because there isn't one.
新型冠状病毒持续在中国肆虐，目前为止已经有超过24，000人感染，各国的科学家都在寻找治疗方法。由于当前还没有针对新型冠状病毒（2019-nCoV）的治疗方法，许多确诊患者无法得到特定的治疗。

In fact, none of the handful of coronaviruses known to infect humans has an approved treatment, and people who are infected typically receive care mainly to help relieve symptoms, according to the U.S. Centers for Disease Control and Prevention (CDC). However, a handful of repurposed drugs, from drugs targeting Ebola to HIV, have already shown promise, according to new findings.
美国疾病预防控制中心（简称美国疾控中心）称，事实上，已知的几个有传染性的冠状病毒都还没有获得批准的治疗方法，感染者现在接受的治疗主要是帮助他们缓解症状罢了。但是根据最新的研究显示，少部分原用于治疗埃博拉病毒和艾滋病病毒的再利用药物是有发展前景的。

Repurposing antivirals
抗病毒药物的再利用

Until recently, there were very few effective antivirals, said Stephen Morse, a professor at Columbia University's Mailman School of Public Health. That was especially true for RNA viruses — like 2019-nCov and HIV — which use RNA, rather than DNA, as their genetic material, Morse said.
哥伦比亚大学梅尔曼公共卫生学院的斯蒂芬·莫尔斯（Stephen Morse）教授称，直到最近，有效的抗病毒药物仍然很少有。这对于2019-新型冠状病毒和艾滋病病毒这类RNA病毒而言尤为如此——它们用RNA作为遗传物质，而不是DNA。

That's changing.
然而，这种现象正在悄然改变。

"In recent years, perhaps encouraged by the successful development of HIV anti-virals, which proved it might be feasible to do more, our armamentarium has greatly expanded," Morse said. Even so, developing brand-new drugs requires a huge investment of both time and resources, he added. So "while you're waiting for the new miracle drug, it's worthwhile looking for existing drugs that could be repurposed" to treat new viruses, Morse told Live Science.
莫尔斯表示：“最近几年可能是受到艾滋病抗病毒药物顺利研发的鼓励——这使得我们可做的更多了，我们在医疗设备上的投入大幅度地增加。”即便如此，研发新型药物需要投入大量时间和人力资源，他补充道，所以“与其等待新药物发生奇迹，不如去寻找可以再利用的现有药物”来治疗新的病毒，莫尔斯接受《科学现场》采访时坦言。

That's exactly the route doctors took to treat a 35-year-old man in Washington state, the first U.S. patient to have been infected with the new coronavirus. When his symptoms worsened, the man was given an unapproved antiviral drug called remdesivir that was originally developed to treat Ebola, according to a case report published Jan. 31 in The New England Journal of Medicine.
这也正是医生们治疗第一名在美确诊感染新型冠状病毒患者的思路——该男子今年35周岁，来自美国的华盛顿州。根据《新英格兰医学期刊》于1月31日公布的病例报告显示，由于该男子病情恶化，医生对其使用了尚未获批的抗病毒药物瑞德西韦（remdesivir）——该药物原本用于治疗埃博拉病毒。

Doctors gave this drug to the patient by making a "compassionate use" request to the Food and Drug Administration (FDA),  which allows experimental drugs to be given to people outside of clinical trials, usually in emergency situations. The patient, who was recently released from the hospital, didn't seem to experience any side effects of the drug.
医生们最终能够对该病人使用这一药物的原因是因为，他们向美国食品药品监督管理局（FDA）提出了“同情用药”的请求——“同情用药”通常用于紧急情况，旨在为常规临床试验之外的患者提供试验性药物治疗。目前，该病人已于近期出院，并且未出现任何药物副作用。

In animal models, scientists have found that remdesivir can knock down similar coronaviruses, such as the ones that cause Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). Despite its use in an emergency situation, the drug "has not been demonstrated to be safe or effective for any use," Gilead Sciences, the biopharmaceutical company that is developing the drug, said in a statement.
研究者们发现，在动物实验中瑞德西韦可以击败相似的冠状病毒，例如造成中东呼吸综合征（MERS）以及严重急性呼吸道综合症（SARS）的冠状病毒。然而，正在研制该药物的生物制药公司吉利德科学公司（Gilead Sciences）在他们的声明中表示，除了在紧急情况时使用，该药物“尚未被证明在任何情况都是安全有效的。”

Viral battles in the lab
实验室的病毒战争

Recently, a group of researchers tested a number of antivirals in the lab for their effectiveness against the new coronavirus. They found that remdesivir stopped the virus from replicating in a lab dish. Similarly, the group found that chloroquine — an approved and widely used anti-malarial and autoimmune disease drug — was also effective in stopping the virus from spreading in human cells in the lab, the researchers reported in a short letter published Feb. 4 in the journal Cell Research. What's more, both drugs were effective at low concentrations, and neither drug was highly toxic to human cells.
近日，一个研究团队在实验室内测试了一些抗病毒药物的有效性。他们在一个培养皿中发现，瑞德西韦阻止了病毒的自我复制。研究人员于2月4日又在《细胞研究》（Cell Research）发文称，他们在实验过程中发现，氯喹作为一种已经获批上市且被广泛用来治疗疟疾和自身免疫性疾病的药物，同样能够高效地阻止新型冠状病毒在人体细胞中繁殖。更值得一提的是，两种药物在低浓度使用时均有效，同时二者不会对人体细胞造成很大的伤害。

"These findings were encouraging but not entirely surprising" because of the previous testing in Ebola patients, cell cultures and animal models, said Fanxiu Zhu, a professor in the Department of Biological Science at Florida State University who was not part of the study. Both drugs "maybe are worthy of trial in this unprecedented and devastating situation," Zhu told Live Science.
鉴于此前已经有过对埃博拉病毒患者、细胞培养及动物模型的相关测试，佛罗里达州立大学生物科学学院的教授朱凡秀（音译）称 ，“这些发现鼓舞人心，但还不达不到让人惊喜的程度”。然而，该教授也向《科学现场》坦言，他认为眼下这两种药物“在空前骇人的情况下是值得一试的。”据悉该教授并非研究团队中的一员。

Though researchers expected the drugs to work, this group effectively proved they did, at least in the lab, in a short time frame, Morse said. Chloroquine "seems to need a higher concentration than remdesivir, but it's within the feasible range, and if it really works as well as the published in vitro results, it would be quite promising," he said.
莫尔斯说，虽然研究人员预计到这些药物会有所帮助，但研究团队还是在短时间内就高效地证实了它们至少在实验中确实派上了用场。他还表示，氯喹“似乎所需浓度比瑞德西韦要高，但尚在可行范围内。如果它真的能像已发表的体外实验结果那样有效，那么战胜病毒便指日可待了。”

Despite those results, testing antivirals in lab dishes "is the beginning, not the end of the process," Morse said. If it works in the lab, or even in animal models, "that's no guarantee it will work in a human patient." Gilead Sciences is now working with health officials in China to establish clinical trials to test the effect of remdesivir on patients infected with the new coronavirus, according to their statement.
莫尔斯认为，尽管有了上述的实验结论，但在实验室培养皿中测试抗病毒药物“仅仅只是开始，而不是结束。”如果在实验室中的试验成功了，甚至在动物模型中也取得了成效，“那也未必能保证它对人类患者一定有用。”根据吉利德科学公司发表的声明，目前他们正与中国的卫生官员合作，试图建立临床试验以测试瑞德西韦对新型冠状病毒感染者的治疗效果。

"I think that there's a lot of hope with remdesivir having some effect, and I think we'll only find that out from clinical trials," said Dr. Amesh Adalja, an infectious-disease specialist and a senior scholar at the Johns Hopkins Center for Health Security in Baltimore.
阿梅什·阿达尔贾（Amesh Adalja)博士是巴尔的摩约翰霍普金斯卫生安全中心(Johns Hopkins Center for Health Security)的传染病专家、高级学者，在他看来：“虽然瑞德西韦很有希望起到积极的作用。但至于这种作用如何，我们只能在临床试验中寻找答案。”

The molecular standoff  
分子僵局

But viruses aren't as easy as bacteria to treat. That's because viruses are very diverse, with unique characteristics that can't be targeted with a broad-spectrum drug like a general antibiotic, Adalja said. Also, viruses use human cellular machinery to create proteins that help it replicate, so targeting the viruses while not damaging human cells can prove challenging, he added.
但是病毒并不像细菌那么好治。阿达尔贾说，这是因为病毒种类繁多，性质独特，不能用普通抗生素之类的广谱药来对付。此外，他还补充道，病毒利用人类的细胞机制来制造蛋白质，从而复制更多的病毒基因。因此，人们很难在不损害人体细胞的情况下将攻击的目标对准病毒本身。

When a virus infects the body, it first finds a cell and latches onto a protein on the cell's surface called a receptor. The virus then enters the cell via a vesicle called an "endosome." From inside this vesicle, it releases its RNA into the cell's cytoplasm and two things happen: the virus hijacks the human cell's machinery to produce the viral proteins needed for replication and it uses its own viral enzyme to copy its RNA. Finally, the viral proteins and RNA assemble into a structure that lets the virus leave the cell and move on to infecting the next cell.
病毒要想感染人体，首先它要找到一个细胞，附着在细胞表面一种叫做受体的蛋白质上，然后通过一个叫做“核内体”的囊泡进入细胞。在囊泡内部，病毒将RNA释放到细胞的细胞质中后就会发生两件事：一是病毒利用人类细胞机制来生产复制所需的病毒蛋白质；二是病毒将使用自己的病毒酶来复制RNA。最后，病毒蛋白质和RNA组合成新的病毒颗粒，分泌到细胞外，继续感染新的细胞。

Antivirals target various points in this process of viral replication, said Carol Shoshkes Reiss, a professor of biology and neural science at New York University. Chloroquine blocks the virus's ability to acidify endosomes and release its RNA into the cell, which is a critical step for most viruses to begin their infection. Remdesivir, in contrast, acts like a nucleotide — the building blocks for RNA — and squishes itself into the copied RNA sequence, creating a "typo" and rendering it useless, Reiss said.
纽约大学（New York University）生物学和神经科学教授卡罗尔·舒克斯·莱斯（Carol Shoshkes Reiss）表示，研发抗病毒药物要针对病毒复制过程中的不同点来做。氯喹不仅防止病毒酸化核内体，还能阻止病毒向细胞释放RNA，这是大多数病毒开始感染人体的关键步骤。莱斯认为，相比之下，瑞德西韦就像核苷酸一样——像栋楼阻塞着RNA的通行——它把自己压缩到复制RNA序列中，破坏RNA的构建，从而使其失效。

When a similar coronavirus caused a SARS outbreak in 2003, some evidence suggested that another class of drugs called “protease inhibitors” approved to treat HIV could also be effective against the SARS coronavirus, Adalja said. Based on previous studies that showed possible benefit of these drugs in treating both SARS and MERS, two of them are now being tested for their ability to treat 2019-nCov in a clinical trial in China, according to an article published in the journal JAMA. These are drugs that target yet another point in viral replication: They block the ability of protein called the "protease" to cut a very long nonfunctional protein into smaller proteins that are needed for the virus to replicate.  
阿达尔贾认为，当非典（一种由类似的冠状病毒而引发的非典型性肺炎）在2003年大爆发时的就有一些证据表明，另一类被批准用于治疗艾滋病病毒的“蛋白酶抑制剂”也能有效治疗引发非典的冠状病毒。根据《美国医学会杂志》(JAMA)出版的一篇期刊论文显示，基于此前的研究，这些药物可能对治疗严重急性呼吸道综合症（SARS)和中东呼吸综合征（MERS)有积极的治疗效果。为了测试它们对新型冠状病毒的疗效，目前中国正在使用其中两种药物以进行临床试验。这两种药物针对的是病毒复制过程的另一个关键点：它们阻断了一种叫做“蛋白酶”的蛋白质，这种蛋白质可以将一种很长的无功能蛋白质切成病毒复制所需的更小的蛋白质。

The Chinese government previously suggested that people infected with the coronavirus should take two lopinavir/ritonavir pills (the protease inhibitors that are currently being tested for use with the novel coronavirus in the Chinese clinical trial) and inhale an interferon (nebulized alpha-interferon) twice a day. Interferon alphas are already approved to treat diseases such as multiple sclerosis and hepatitis C.
中国政府此前建议，冠状病毒感染者应每日服用两粒洛匹那韦/利托纳韦（lopinavir/ritonavir）（目前这种蛋白酶抑制剂在中国临床试验中用于测试其对于新型冠状病毒的抑制作用），同时每日吸入干扰素（雾化α-干扰素）两次。α-干扰素已被批准用于治疗多发性硬化症和丙型肝炎等疾病。

These drugs induce interferons, proteins that human cells naturally release as an alarm to other cells that there is an infection in the body. Interferons are very useful because they aren't specific to a single virus but respond to all viruses and all stages of viral replication, Reiss said.
这些药物会诱导干扰素以及一种由人体细胞自然释放的蛋白质的产生，这种蛋白质的释放通常会向其他细胞发出体内感染的警报。莱斯说，干扰素非常有用，因为它们不只是针对一种病毒，而是对所有病毒和病毒复制的所有阶段都有反应。

And once researchers identify the specific protein on the outside of human cells that the new coronavirus uses to gain entry, "then they'll be able to find small molecules that can block the binding of the virus into cells," Reiss said. In other words, they might create completely new types of drugs rather than repurpose older ones. "But these will take time to find," Reiss said.
一旦研究人员在人体细胞外部确定了这种新型冠状病毒进入所使用的特定蛋白，“他们就可以找到能够阻止病毒与细胞结合的小分子物质，”莱斯说道。换句话说，他们可能就研发出了新的药物，而不是再利用旧的药物，“但是寻找这些小分子物质是需要时间的。”

Current research is underway in laboratories to do just that. For example, in a collaboration between the U.S. Department of Health and Human Services and Regeneron Pharmaceuticals, scientists are working to identify antibodies that will stop the coronavirus from entering cells, according to a statement. Still others are looking to develop a vaccine: Researchers at the U.S. National Institutes of Health are in the early stages of developing a vaccine and plan to launch a clinical trial within the next three months, according to a statement.
目前，实验室正在对此开展相关研究。一份声明中称，通过美国卫生与公众服务部与再生元制药公司(Regeneron Pharmaceuticals) 的合作，科学家们正在努力识别能够阻止冠状病毒进入细胞的抗体。还有一些人则致力于研制相关的疫苗：据另一份声明中所称，美国国立卫生研究院(National Institutes of Health)正在开发一种疫苗，目前正处于初期阶段，他们计划在未来三个月内开展临床试验。

Cocktail of drugs
混合药物

Instead of finding a single drug to treat the coronavirus, "I would suggest a cocktail of drugs that target different stages of replication," Reiss said. "This virus is probably going to be like a number of other viruses, and it will undergo mutation and selection, so if you use only one antiviral drug, you are going to ultimately select for resistance."
与其寻找单一药物来治疗新型冠状病毒，“我建议采用能够针对病毒复制不同阶段的混合药物，”莱斯称，“这种病毒可能会像其他病毒一样变异、进化，所以如果只采用单一药物进行治疗的话，最终会使其产生耐药性。”

What's more, the treatment will be most effective when given to a patient early on, perhaps even before symptoms develop, she said. "Taken very early in the course of exposure, the antiviral drugs could have a real impact," she said. After someone is already in the hospital in respiratory distress and a high fever, "it is much harder to treat the infection, people are more likely to treat the disease."
莱斯认为，更重要的是，如果能在早期就对患者进行治疗，甚至在症状出现之前，治疗将会是最有效的。“在感染病毒的早期就服用抗病毒药物才会有真正的治疗效果。”就在已经有人因呼吸道困难和高烧症状入院之后，她表示：“治愈疾病本身不难，难的是治愈疾病的传染。”

Treating the disease means lessening the symptoms by providing respiratory support, lowering the fever and making sure people are hydrated, among other things. The vast majority of coronavirus patients today are receiving this type of treatment.
目前，新冠肺炎的治疗方法主要是通过提供呼吸系统治疗、降低体温以及确保人体水分的充足等来减轻症状。绝大多数的确诊患者如今都在使用这种方式进行治疗。

Though several potential antivirals might one day be used to treat the new coronavirus, it will likely take a couple of years for such drugs to be tested and approved. Once they are approved, there will probably be discussion around whether these antivirals should be given to patients to prevent disease or given to patients with relatively uncomplicated cases, similar to the debate around the best use for Tamiflu, Morse said.
尽管的确有几种抗病毒的药物可以在未来被用于治疗这种新型冠状病毒，但这类药物的测试和批准可能需要几年的时间。莫尔斯表示，一旦这些抗病毒药物获得批准很有可能会引发新一轮的讨论——例如这些抗病毒药物应该用于预防疾病，还是应该用于症状较轻的病例，就像是围绕达菲（Tamiflu）（预防及治疗流行性感冒药物）的最佳用途所展开的争论一样。

"A good antiviral, given early enough, could be lifesaving in severe infections with this coronavirus," he said. "It's probably most valuable in severe cases, and we may want to save it for those."
“好的抗病毒药物，若是在发病的初期使用，对于严重感染新型冠状病毒的患者而言是有救命作用的，”他说道，“这种药物的价值最能够在重症病例中体现，我们也许应该把它留给那些重症患者。”

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