“病毒破解”分子推动乙型肝炎的斗争

StephenW

'Virus-cracking' molecules advance fight against hepatitis B                                                                        Date:February 6, 2018Source:Indiana UniversitySummary:Researchers have found that certain molecules -- currently under clinical trial -- are able to 'crack' the protective shell of the hepatitis B virus, suggesting it may be possible to attack the virus after its already taken hold in the body. There is currently no cure for the virus, which can cause liver failure and cancer.Share:                                                                                       
                                       
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                                        This image shows the shell, or capsid, that encapsulates the DNA of the hepatitis B virus, which is composed of 240 copies of the same protein. The green areas depict the structurally unique regions, which are found in a repeated arrangement across the surface of the shell. The small red areas reveal the sites where the molecule HAP binds to the virus.
                                        Credit: Christopher Schlicksup, Indiana University
                                                                                                                                                                       
                                                                                                                       

Indiana University researchers have made an important step forward in the design of drugs that fight the hepatitis B virus, which can cause liver failure and liver cancer.

                                                                                                                                It's estimated that 2 billion people worldwide have had a hepatitis B virus infection in their lifetime, with about 250 million -- including 2 million Americans -- living with chronic infection. Although a vaccine exists, there is no cure.
The study, published Jan. 29 in the journal eLife, explains how the structure of the hepatitis B virus changes when bound to an experimental drug. Members of this new class of antiviral drug are now in clinical trials.
"Our discovery suggests that this same drug could attack hepatitis B virus on multiple fronts -- both preventing replication and killing new copies of the virus," said senior author Adam Zlotnick, a professor in the IU Bloomington College of Arts and Sciences' Department of Molecular and Cellular Biochemistry. "If we're smart, we can take advantage of the multiple ways this drug can work at the same time."
The research was led by Christopher Schlicksup, a graduate student in the department.
A virus reproduces by hijacking a host's cellular machinery to produce more of the virus. The majority of viruses protect their genetic material -- DNA or RNA -- inside a protein shell called a "capsid."
For the past 20 years, Zlotnick's lab has conducted research to stop viral infections by studying the physics of viruses, focusing on how capsids are formed.
"The reaction is a bit like throwing a deck of cards in the air to build the Taj Mahal -- a highly complex structure seemingly emerging from chaos," Zlotnick said. His work helped discover a class of molecules called core protein allosteric modulators, or CpAMs, that disrupt capsid protein assembly.
                                                CpAM molecules attack viruses by causing their shells to assemble incorrectly, interrupting the life cycle of the virus. Previously, CpAMs were seen as only able to disrupt a virus during formation of the capsid, after which its DNA was protected inside a hard casing.
This new study finds the molecule can break apart this shell even after it has already assembled.
To make their discovery, IU scientists bound the CpAM to a chemical called TAMRA -- a crimson-colored dye used in some red lipstick -- to make it fluorescent and easier to detect in experiments. Using cryo-electron microscopy, they found the small CpAM molecule could make the large, soccer ball-shaped virus capsid bend and distort.
"The big implication is viral capsids aren't as impenetrable as previously thought," Zlotnick said. "The other implication, which may be even more important, is that if this type of interference works against hepatitis B virus, it might also work against other viruses.
"About half of known virus families have soccer ball-like capsids; examples include polio and herpes," he added. "This study may lead to better treatments against them since the mechanisms behind capsid disruption could lead to drugs against any of them."
Zlotnick also is the co-founder of Assembly Biosciences, a NASDAQ-listed company, which has CpAMs in clinical trials. Although the molecule used in this study isn't one of the molecules under clinical trial, Zlotnick said the mechanism sheds light on the behavior of the experimental drugs. Next, Zlotnick hopes to conduct similar studies on the CpAMs under clinical trial.

                                                                                                                                               

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Journal Reference:

• Christopher John Schlicksup, Joseph Che-Yen Wang, Samson Francis, Balasubramanian Venkatakrishnan, William W Turner, Michael VanNieuwenhze, Adam Zlotnick. Hepatitis B virus core protein allosteric modulators can distort and disrupt intact capsids. eLife, 2018; 7 DOI: 10.7554/eLife.31473
  

StephenW

“病毒破解”分子推动乙型肝炎的斗争

日期：
    2018年2月6日
资源：
    印第安纳大学
概要：
    研究人员发现，目前正在临床试验中的某些分子能够“破解”乙型肝炎病毒的保护壳，这意味着它有可能在病毒已经进入体内之后对其进行攻击。目前还没有治愈的病毒，可能会导致肝衰竭和癌症。
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完整的故事
这张图片显示了包装乙型肝炎病毒DNA的壳或衣壳，其由240个相同的蛋白质组成。绿色区域描绘了结构上独特的区域，这些区域在壳体表面的重复排列中被发现。小的红色区域显示分子HAP与病毒结合的位点。
信用：印第安纳大学的克里斯托弗·施克里克斯普

印第安纳大学的研究人员在设计抗乙型肝炎病毒的药物方面迈出了重要的一步，可能导致肝衰竭和肝癌。

据估计，全世界有20亿人在其一生中感染了乙型肝炎病毒，其中约2.5亿人 - 包括200万美国人 - 患有慢性感染。虽然有疫苗存在，但没有办法治愈。

这项于1月29日在eLife杂志上发表的研究解释了乙型肝炎病毒的结构在与实验药物结合时如何改变。这类新型抗病毒药物的成员正在临床试验中。

资深作者Adam Zlotnick是IU布卢明顿艺术与科学学院系教授，他说：“我们的发现表明，同样的药物可以在多个方面攻击乙型肝炎病毒，包括防止复制和杀死新病毒。分子和细胞生物化学。 “如果我们很聪明，我们可以利用这种药物同时工作的多种方式。”

研究由该系研究生Christopher Schlicksup领导。

病毒通过劫持宿主的细胞机器再生产更多的病毒。大多数病毒保护着他们的遗传物质 - DNA或RNA--在一个称为“衣壳”的蛋白质壳内。

在过去的20年里，Zlotnick的实验室通过研究病毒的物理学来研究阻止病毒感染，重点是如何形成衣壳。

Zlotnick说：“这个反应有点像在空中扔了一副牌子来建造泰姬陵 - 这个非常复杂的结构似乎正在摆脱混乱。他的工作帮助发现了一类称为核心蛋白质变构调节剂或CpAMs的分子破坏衣壳蛋白组装的分子。

CpAM分子通过使其外壳不正确地组装来攻击病毒，从而中断了病毒的生命周期。以前，CpAM被认为只能在衣壳形成过程中破坏病毒，然后在坚硬的肠衣内保护其DNA。

这项新的研究发现，即使已经组装，分子也可以分解这个壳。

为了让他们发现，IU科学家们将CpAM与一种叫做TAMRA（一种红色唇膏中使用的绯红色染料）的化学物质结合起来，使其在实验中更具荧光性，更易于检测。他们使用低温电子显微镜，发现小CpAM分子可以使大的足球形病毒衣壳弯曲和变形。

Zlotnick说：“大的含义是病毒衣壳不像以前想象的那样难以穿透。 “另一个可能更重要的含义是，如果这种类型的干扰对抗乙型肝炎病毒，它也可能对付其他病毒。

他补充说：“大约有一半的已知病毒家族都有类似足球的衣壳，例如脊髓灰质炎和疱疹。 “这项研究可能导致对他们更好的治疗，因为衣壳破裂背后的机制可能导致毒品对他们中的任何一个。

Zlotnick也是纳斯达克上市公司Assembly Biosciences的联合创始人，该公司在临床试验中拥有CpAMs。尽管本研究中使用的分子不是临床试验中的分子之一，但Zlotnick说这种机制揭示了实验药物的行为。接下来，Zlotnick希望对临床试验中的CpAMs进行类似的研究。

故事来源：

物料
由印第安纳大学提供。注意：内容可能会根据样式和长度进行编辑。

期刊参考：

    Christopher John Schlicksup，Joseph Che-Yen Wang，Samson Francis，Balasubramanian Venkatakrishnan，William W Turner，Michael VanNieuwenhze，Adam Zlotnick。乙型肝炎病毒核心蛋白变构调节剂可以扭曲和破坏完整的衣壳。 eLife，2018年; 7 DOI：10.7554 / eLife.31473

newchinabok

2020前后有一款核衣壳抑制剂上市，个人估计

windu

这样看来，核衣壳类的药物很有前途

jdcy

顶！