广谱抗病毒药物的潜力可能存在于宿主细胞内

StephenW

广谱抗病毒药物的潜力可能存在于宿主细胞内
海伦·弗洛尔什
2022 年 10 月 12 日下午 12:21
抗病毒抗病毒药物俄亥俄州立大学学术研究
巨细胞病毒，CMV，疱疹，疱疹病毒，病毒
在患有呼吸道病毒的小鼠中敲除 NSUN2 基因会降低病毒基因的表达并增加干扰素水平。 (Dr_Microbe/iStock/Getty Images Plus)

抗病毒药物开发的世界主要在一个简单的范式下运作：一种错误，一种药物。也就是说，大多数疗法旨在针对特定病毒特有的蛋白质，例如用于丙型肝炎的 COVID-19 疫苗或特拉匹韦。

长期以来，科学家们一直在寻找通过攻击在多种类型的错误中保守的机制来扩大抗病毒药物适应症的方法。现在，来自俄亥俄州立大学的一组研究人员发现了一种酶，当被抑制时，这种酶可以减缓病毒复制并改善感染多种病毒的小鼠的结果。他们的工作结果于 10 月 10 日发表在《美国国家科学院院刊》上。

靶向酶 NSUN2 参与了一个修饰 RNA 的过程——称为 5-甲基胞嘧啶甲基化——从而调节多种生物学途径。几十年前，研究 5-甲基胞嘧啶甲基化的科学家认为 NSUN2 存在于病毒中。然而，通过使用更新的转录组作图技术，俄亥俄州立大学的研究人员表明该过程发生在哺乳动物细胞中。作图结果表明，5-甲基胞嘧啶甲基化也会导致免疫反应的抑制。

为了验证这一点，研究人员在培养细胞和人肺模型中敲低了 NSUN2 的基因。这样做会导致产生 1 型干扰素，这是对先天免疫反应至关重要的细胞因子。当他们针对这些细胞测试多种病毒时——包括三种已知会导致人类和小鼠出现严重呼吸道疾病的病毒；水疱性口炎病毒，可导致牛的严重疾病和单纯疱疹 1 型病毒——他们发现病毒复制和基因表达减少。

“如果你能检测到这种修改，那么你就可以研究它并瞄准它，”共同资深作者川河博士在一份新闻稿中说。 “事实证明，这里的关键不是病毒 RNA 修饰，而是宿主 RNA 修饰，它会触发宿主免疫反应。”

结果在老鼠身上也成立。在患有呼吸道病毒的小鼠中敲除 NSUN2 基因会降低病毒基因的表达并增加干扰素水平。实验小鼠的肺部病变也比对照组少。水泡性口炎病毒也是如此；通常能够在 24 小时内杀死宿主细胞，但在没有 NSUN2 基因的小鼠中，该病毒几乎被完全消灭。

阻断 NSUN2 究竟是如何刺激免疫反应的？当酶被抑制时，它会暴露宿主 RNA 片段。先天免疫系统将它们视为外来入侵者，释放出一种 1 型干扰素反应，一旦达到足够的水平，就会同时对抗病毒。

接下来，科学家们计划开发一种抑制 NSUN2 功能的药物。他们还计划看看相同的机制是否可以对抗另一个众所周知的敌人：COVID-19。

StephenW

Potential for broad-spectrum antivirals could lie within host cells
By Helen Floersh
Oct 12, 2022 12:21pm
antiviralantiviral drugOhio State Universityacademic research
Cytomegalovirus, CMV, herpes, herpesvirus, virus
Knocking down the gene for NSUN2 in mice with a respiratory virus reduced the expression of viral genes and increased interferon levels. (Dr_Microbe/iStock/Getty Images Plus)

The world of antiviral drug development largely operates under a simple paradigm: one bug, one drug. That is, most therapies are designed to target proteins that are unique to specific viruses, such as the COVID-19 vaccine or telaprevir for hepatitis C.

Scientists have long searched for ways to expand antivirals’ indications by attacking mechanisms that are conserved across multiple types of bugs. Now, a team of researchers from Ohio State University have identified an enzyme that when inhibited, slowed viral replication and improved outcomes in mice infected with a wide range of viruses. The results of their work were published Oct. 10 in the journal Proceedings of the National Academy of Sciences.

The targeted enzyme, NSUN2, is involved in a process that modifies RNA—called 5-methylcytosine methylation—and thereby regulating multiple biological pathways. Decades ago, scientists studying 5-methylcytosine methylation thought NSUN2 was found in viruses. However, by using newer transcriptome mapping techniques, the Ohio State researchers showed that the process takes place in mammalian cells instead. The mapping results suggested that 5-methylcytosine methylation would lead to suppression of the immune response, too.

To verify this, the researchers knocked down the gene for NSUN2 in cultured cells and human lung models. Doing so led to the production of type 1 interferon, cytokines that are vital to the innate immune response. When they tested multiple viruses against the cells—including three known for causing severe respiratory disease in humans and mice; vesicular stomatitis virus, which can cause serious disease in cattle and the herpes simplex type 1 virus—they found that viral replication and gene expression was reduced.

“If you can detect the modification, then you can study it and target it,” Chuan He, PhD, co-senior author, said in a press release. “It turns out the key here is not a viral RNA modification, but a host RNA modification, and it triggers a host immune response.”

The results held up in mice too. Knocking down the gene for NSUN2 in mice with a respiratory virus reduced the expression of viral genes and increased interferon levels. The experimental mice also had fewer lung pathologies than controls. And the same was true for vesicular stomatitis virus; normally able to kill host cells within 24 hours, the virus was almost completely wiped out in mice without the gene for NSUN2.

How does blocking NSUN2 stimulate the immune response, exactly? When the enzyme is suppressed, it exposes host RNA snippets. The innate immune system sees them as foreign invaders, unleashing a type 1 interferon response that, once it reaches a sufficient level, tackles the virus at the same time.

Next, the scientists plan to develop a drug that suppresses NSUN2’s function. They also plan to see if the same mechanism might work against another well-known foe: COVID-19.