圣路易斯大学乙型肝炎的研究取得了决胜性的成果

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        乙型肝炎（下称乙肝）的治愈，将会减少全球肝癌的发生

        圣路易斯——1月24日出版的《美国科学图书馆病原体》发表了一项研究的论文，圣路易斯大学（SLU）的研究人员与密苏里大学和匹兹堡大学的合作者们一起报告，他们在寻找可消除病毒和治愈乙肝的新药中，取得了突破性的进展。研究人员，现在利用一种主要病原体艾滋病毒（HIV）的已知类似知识，已能测定以前未曾研究过的一种酶，并能阻断它的活性，以阻止病毒的复制。

        SLU的分子微生物学和免疫学教授和本研究论文的作者约翰·塔费斯（John Tavis）哲学博士说，这一研究结果可能导致新药的产生，这种新药与现有的药物相结合，可能抑制病毒并足以治愈患者。

        塔费斯说：“乙肝是全球肝功能衰竭和肝癌的主要原因。本研究结果，对肝脏疾病和肝癌的发病率的降低，将会有非常有益的作用。”

        “如果我们能治愈乙肝，我们就可以消除大部分的肝癌病例。这项研究，是向着这个目标迈进了一步。”

        世界卫生组织估计，有超过3亿5千万人被乙肝病毒（HBV）慢性感染。尽管有些药物不能使许多患者治愈，不过仍能成功地消除患者的症状。那些感染了HBV的人，每年死于肝功能衰竭和肝癌的有120万。

        感染HBV的人，每滴血液中可以有多达10亿的病毒拷贝数。为了治愈一个患者，需要用一种药物把这个水平降低到零。

        现在的药物不能完全治愈乙肝

        虽然，现有的药物是很有效的，但它们也不能完全治愈乙肝。这些被批准用于治疗乙肝的药物，可以减少病毒的数量，使症状消失多年，甚至使HBV濒临灭绝。但对于大多数人来说，现有的药物不能够完全杀死病毒。而且，任何保存下来的病毒，在条件适宜时，它仍可以强盛地增殖。

        所以，乙肝的治疗通常地要持续几十年，如果患者能负担得起医药费，其每一个月的费用需要400~600美元。治疗费用的昂贵，超出了许多人的平均承受能力，以致一些患者就完全不接受任何治疗。作为一个折中的措施，一些患者选择服一个短时期的药，使疾病的损害暂时缓解几年。

        一个19 年的困惑

        同样，在实验室中对HBV进行着持续地研究。塔费斯直至不久前，一直对HBV遗传之谜特殊部分的研究，已进行了19年，用他自己的话说，经受了不断失败的痛苦。

        这是实验室中一个常见的问题。科学家们在能够对这个遗传之谜度量之前，他们是无法对它进行研究的。而且，直至研究人员有了一些小成功时，他们仍然不知道是否在正确的轨道上或走向了死胡同。

        塔费斯认为，这种情况可从特定的酶得到答案。多年来，他一遍又一遍地对这一难题进行着反复的研究。

        塔费斯说：“直到你看见第一线微弱的闪光之前，所有的底片看起来都是一样的。”“在这项工作中，最高超的技能之一，就是知道什么时候该放弃。这不是很明显的，什么时候你是在浪费时间，什么时候你放弃得太早。”

       

       

        就塔费斯来说，他的本能使他工作得很好，在两年以前，他看到了正在寻找的答案的第一线微弱的闪光。

        病毒的策略

        塔费斯说：“病毒是基因组的行李箱。”“它们有许多侵入我们的细胞并以它们自己DNA为蓝图接管我们细胞的策略。”

        就HBV来说——也像HIV一样实现了一个幸运的突破——HBV是通过逆转录复制的。在这个过程中，病毒的DNA转换成RNA，然后RNA在两种病毒酶的作用下，再转换成DNA，这两种酶对病毒的复制都是极其重要的。

        两种酶中的第一种是DNA聚合酶，在实验室中已进行了很好的研究。5种最常用的药物，通过阻断DNA聚合酶的作用来治疗（但不能治愈）乙肝。

        第二种酶是核糖核酸酶H（RNAseH），实验室里的研究人员都难以进行研究。因为没有办法来度量它，即使在理论上，他们认为这种酶是一个有前途的靶标，它成了研究人员研究的死角。

        这样，已经批准的针对第一种酶的药物有5种，而针对第二种酶的药物且没有1种，所以塔费斯对RNAseH的研究持续地进行了近20年。

        寻找一种测定的方法

        塔费斯不断地寻找可用得上的衡量标准。

        虽然，针对RNAseH是有道理的，但是没有现存的方法可以测定它的活性。塔费斯一直在寻找一种测定方法，可以告知一种物质是否能阻断这种酶的功能。

        经过多年的研究以后，塔费斯和他的研究团队看到了酶活性的一线微弱的闪光，并开发出一种测定RNAseH的方法，使他开始研究这种酶，和检验关于如何阻断这种酶的有希望的理论。

        从HIV的研究成果中得到借鉴

        由于HBV和HIV二者均是采用逆转录机制增殖的，通过这种机制，它们在人体细胞中自我复制，乙肝研究人员已可从HIV研究的进展中得到益处。自从HIV发现以来，由于大量资金的投入，对它的研究取得了迅猛的进展。针对逆转录过程的几个治疗HIV有效的药物，也具有抗HBV的作用。

        虽然这两种病毒是非常地不同，塔费斯和他的同事们、密苏里大学的斯特凡·塞雷非亚斯（Stefan Sarafianos）哲学博士和匹兹堡大学的迈克尔·帕尼亚克（Michael Parniak）哲学博士认为这种共有的过程，提示应该有一些可以利用的化学相似性。

        “正如每一辆汔车有一些轮胎和一台发动机一样，这两种病毒也有几件具有一些相似功能的组分。你可以把一辆汔车的发动机安装到另一辆汔车上试用。它可能不够完善地适合，但它应可发挥相同的功能。”

        检测RNAseH的方法一开发出来，塔费斯和他的团队就可检验这种理论了。

        塔费斯说：“我们发现第一种酶和第二种酶都在发挥作用。”“这是一种原理性的证明。我们的研究在正确的轨道上前进。”

        塔费斯现在有了一个度量的工具，以及包括阻止HIV复制的HIV RNAseH的抑制剂也能抑制HBV RNAseH的若干技术证据，这表明两种病毒RNAseH的相似性是真实的。据此，塔费斯和他的团队继续证明HBV在细胞中的复制，确实是可以用针对难以捉摸的第二种酶（RNAseH）的药物来阻止。

        已经有了希望的苗头

        研究人员说，根据这些前景看好的进展，现在寻找抗乙肝RNAseH药物是可行的，并且，使用类似的抗HIV化合物作为一种导向，可能会有高的成功机会。

       

        研究团队的下一步，将研究HBV不同基因型的几个变异，以致能够测定和研究各种类型的RNaseH。目前的研究结果证明，只在几个基因型中取得了成功。根据目前的研究提示，研究人员试图阻断RNAseH的作用，现在两种最常见的基因型B和C之中，已找到了一些有希望的途径。

        此外，研究人员将致力于提高高通量筛选检测过程的强度和速度，从成千上万化合物中快速筛选出能阻断RNAseH的药物。这些发展，将会使从全方位来发现抗病毒药物的路变得清晰起来。

        研究人员们有理由希望，把一种新的抗乙肝RNAseH药物与现有的药物结合起来使用，可能抑制HBV并足以治愈乙肝患者。

        塔费斯说：“我预计，一种针对第二种酶的新药将与现有的药物一起使用，它们分别阻断病毒复制过程的不同部分。”

        ‘我们已有一些很好的药物。它们可以抑制但不可能完全杀灭HBV。它们的功能在未来仍然难以提升，但与另一个药物相结合，我希望我们将能把其余的病毒消除干净。它们结合在一起，这个目的是可能达到的。我们达到这一点，是没有太远的距离了。“

        塔费斯的研究，是由圣路易斯大学校长研究基金、圣路易斯大学之友肝脏中心和圣路易斯大学癌症中心资助的。

        从中得出的结论：

        · 目前针对乙肝的药物，可用于治疗，但不能治愈大多数人的感染。圣路易斯大学研究人员的新突破，为另一种可有助治愈那些感染者的药物的开发铺平了道路。

        · 研究人员利用与另一个重要病原体HIV已知的相似性，已能测定一种先前未曾研究过的酶，并阻断它，致使HBV不能复制。

        · 寻找抗HBV RNAseH药物，现在是可行的。使用类似的抗HIV化合物，可能会有一个高的成功机会。

        · 因为世界上大部分肝癌病例是由HBV造成的，乙肝的治愈将会大幅度地降低肝癌的发病率。

        · 正如所有的实验室研究一样，一种治疗药物在批准可用于治疗之前，是需要经过更多研究的。此外，实验室研究的任何一种新药，都将必须在临床试验中，研究了解它的安全性和有效性是怎样的。

        ·圣路易斯大学医学院，建立于1836年，在密西西比河以西地区，第一个具有授予医学学位资格的荣誉。学院培养医师和生物医学科学家，组织实施医学研究，并为当地、国内和国际提供医疗保健服务。学院寻求5个最重要领域中新的治愈和治疗技术：癌症、肝脏疾病、心脏/肺脏疾病、衰老和大脑疾病以及传染性疾病。

jsmscym

看来治愈乙肝指日可待，这个消息不会是假的。

才易的生活

谢谢楼主，请楼主继续跟踪关注

hchu

回复 jsmscym 的帖子

是的。问题是在于如何加快新药物的问世速度。可惜中国的研究机构在这方面毫无作为。

sddp1

这是新年最好的礼物了。

精彩继续

乙肝攻克应该也就在这3,5年内啦

hchu

“研究人员将致力于提高高通量筛选检测过程的强度和速度，从成千上万化合物中快速筛选出能阻断RNAseH的药物。”

以上一点，中国的研究机构能帮得上忙吗？快速筛选工作不妨人海战术。

咬牙硬挺

加油吧，我已经不着急了

海上明月光

没看懂，是说dna药物防止复制，rna药物防止感染吗？

寻梦人

In a Fight to the Finish, Saint Louis University Research Aims Knockout Punch at Hepatitis B




A Cure for the Virus Would Reduce Liver Cancer Worldwide




ST. LOUIS – In research published in the Jan. 24 edition of PLOS Pathogens, Saint Louis University investigators together with collaborators from the University of Missouri and the University of Pittsburgh report a breakthrough in the pursuit of new hepatitis B drugs that could help cure the virus. Researchers were able to measure and then block a previously unstudied enzyme to stop the virus from replicating, taking advantage of known similarities with another major pathogen, HIV.







John Tavis, Ph.D. is professor of molecular microbiology and immunology at SLU.


John Tavis, Ph.D., study author and professor of molecular microbiology and immunology at SLU, says the finding may lead to drugs which, in combination with existing medications, could suppress the virus far enough to cure patients.

“Hepatitis B is the major cause of liver failure and liver cancer worldwide,” Tavis said. “This would have an extremely positive effect on liver disease and liver cancer rates.

“If we can cure hepatitis B, we can eliminate the majority of liver cancer cases. This research is a step toward achieving that goal.”

World health experts estimate that more than 350 million people are chronically infected with the hepatitis B virus. Several drugs are able to treat symptoms successfully, though they are not able to cure many patients. Of those infected with hepatitis B virus, up to 1.2 million die from liver failure and liver cancer each year.

A person who is infected with hepatitis B virus can have up to a billion viral copies per drop of blood. To cure a patient, a drug needs to reduce those levels to zero.

Not Quite a Cure
While existing medications are very powerful, they cannot quite deliver the knockout punch to hepatitis B. The drugs approved to treat the virus can reduce its numbers, make symptoms disappear for years and push it to the brink of extinction. But for most people, the medications can’t kill the virus completely. And, as long as any virus remains, it can multiply and grow strong again.

And so, hepatitis B treatment usually spans decades, with costs of $400 to $600 a month, if patients can afford the medication. Expensive and beyond the means of many, some patients do not receive any treatment at all. As a compromise measure, some patients opt to take medication for a short time, staving off the damage the illness will cause for a few years.

A 19-Year Puzzle
Hepatitis B virus puts up a protracted fight in the lab, as well. For 19 years, Tavis has worked on a particular part of the virus’s genetic puzzle, and until recently he had been, in his words, failing miserably.

The problem was a common one in the laboratory. Until scientists can measure a puzzle piece, they can’t study it. And, until researchers have some small success, they don’t know if they’re on the right track or headed down a dead end.

This was the case for the particular enzyme Tavis believed held answers. Stumped, he returned to the puzzle again and again over the years.

“Until you see that first glimmer, all negatives look the same,” Tavis said. “One of the biggest skills in this job is knowing when to give up. It’s not obvious when you are wasting time and when you are giving up too early.”

In Tavis’s case, his instinct served him well, and two years ago, he saw the first glimmer of the answer he was searching for.

A Virus’s Tactics
“Viruses are genomic suitcases,” Tavis said. “They have many tactics for invading and taking over our cells, using their own DNA as the blueprints.”

In the case of hepatitis B virus, and, -- in what turned out to be a lucky break, HIV, as well -- the virus replicates by reverse transcription. In this process, viral DNA is converted to RNA and then converted back to DNA by two viral enzymes, both of which are vital to the virus’s replication.

The first of these enzymes, a DNA polymerase, has been well studied in the lab. The five most commonly used hepatitis B drugs are able to treat (but not cure) the illness by blocking this enzyme.

The second enzyme, ribonuclease H (RNAseH) had eluded investigators in the lab. With no means to measure it, researchers hit dead ends even though they believed the enzyme was a promising target, in theory.

So, with five approved drugs targeting the first enzyme and none aimed at the second, Tavis sparred with RNAseH for nearly two decades.

Search for an Assay
Tavis was searching for a yardstick, of sorts.

Though it made sense to target RNAseH, no method existed that allowed researchers to measure the enzyme’s activity. Tavis was looking for an assay, a way to tell if a substance would block the enyzme’s function.

After years of work, Tavis and his research team saw the first glimmer of activity and were able to develop an assay for RNAseH, allowing him to begin to study the enzyme and try out promising theories about how to block it.




“Just as every car has tires and an engine, both of these viruses have pieces that serve similar functions.

You can take an engine from one car and try it in the other.It might not be a perfect fit, but it should serve the same function.” --John Tavis  







Borrowing from HIV
Because the hepatitis B and HIV viruses both use reverse transcription, the mechanism by which they copy themselves in the body’s cells, hepatitis B researchers have been able to benefit from advances in HIV research. Thanks to substantial funding, HIV research has made rapid progress since the virus’s discovery. Several effective drugs for HIV treatment work by targeting the reverse transcription process also work against hepatitis B virus.

Though the viruses are quite different, Tavis and his colleagues Stefan Sarafianos, Ph.D. at the University of Missouri and Michael Parniak, Ph.D., at the University of Pittsberg believed that the shared process suggested there should be some chemical similarities that could be exploited.

“Just as every car has tires and an engine, both of these viruses have pieces that serve similar functions. You can take an engine from one car and try it in the other. It might not be a perfect fit, but it should serve the same function.”

Once the assay for the RNAseH was developed, Tavis and his team were able to try out this theory.

“We found that what worked with the first enzyme worked with the second enzyme,” Tavis said. “This is a proof of principle. We’re on the right track.”

Tavis now has a measuring tool and evidence that a number of the techniques that stopped HIV, including inhibitors of HIV RNAseH, could also inhibit the hepatitis B virus RNAseH, showing that the parallels held true. From there, Tavis and his team went on to prove that hepatitis B replication could in fact be stopped in cells with drugs that targeted the elusive second enzyme, RNAseH.

Hope on the Horizon
With these promising advances, researchers say that the search for anti-hepatitis B RNAseH drugs is now feasible and that using similar anti-HIV compounds as a guide is likely to have a high chance of success.

The research team’s next step will be to study several variations of hepatitis B virus, different genotypes of the virus, to be able to measure and study the RNAseH enzyme in all forms of the virus. Current findings demonstrated success in only some genotypes. Findings from the current study suggest some promising avenues as researchers will now attempt to block RNAseH in the two most common genotypes, B and C.

In addition, researchers will aim to improve the strength and speed of the RNAseH assay for high throughput screening, a process for rapidly screening many thousands of compounds. These developments will clear the way for full-scale antiviral drug discovery.

Investigators have reason to hope that combining a new anti-hepatitis B RNAseH drug with the existing drugs may suppress the virus far enough to cure patients with hepatitis B.

“I anticipate a new drug targeting the second enzyme would be used together with the existing drugs,” Tavis said. “They jam different parts of the process.

“The drugs we have are very good drugs. They push the virus down, but they can’t quite kill it. They’ll still do the heavy lifting in the future, but with an additional drug I hope we’ll be able to mop up the rest. Together, they may be able to do it. We don’t have a big distance we need to travel to reach that point.”

Tavis’s research was funded by Saint Louis University’s President’s Research Fund, Friends of the Saint Louis University Liver Center, and the Saint Louis University Cancer Center.

TAKE-AWAYS:
•Current hepatitis B drugs can treat but not cure the infection for most people. Saint Louis University researchers’ new breakthrough paves the way for additional drugs that can help cure those who are infected.
•Researchers were able to measure and then block a previously unstudied enzyme to stop the virus from replicating, taking advantage of known similarities with another major pathogen, HIV.
•The search for anti-hepatitis B virus RNAseH drugs is now feasible. Using similar anti-HIV compounds is likely to have a high chance of success.
•Because the majority of liver cancer cases worldwide are caused by hepatitis B virus, a cure would dramatically cut liver cancer rates.
•As with all laboratory research, more study is needed before a treatment can be approved for patients. In addition to further laboratory research, any new drugs would have to be studied in a clinical trial to know how safe and effective they will be.
Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: cancer, liver disease, heart/lung disease, aging and brain disease, and infectious disease.