CT-2584

在COVID-19大流行的两年多时间里，人们意识到“新常态”包括人类将有可能与SARS-CoV-2长期共存。一些治疗方法是可用的，但随着新变体的出现，科学家们正在寻找新的策略。 在COVID-19大流行的两年多时间里，人们意识到“新常态”包括人类将有可能与SARS-CoV-2长期共存。一些治疗方法是可用的，但随着新变体的出现，科学家们正在寻找新的策略。在一项新的研究中，来自美国佛罗里达大学和瑞士苏黎世大学等研究机构的研究人员指出，靶向人类蛋白Sec61的抗癌候选药物apratoxin S4（Apra S4）可以干扰包括SARS-CoV-2和甲型流感病毒在内的许多病毒的复制，从而可能提供了一种泛病毒疗法。相关研究结果于2022年6月29日在线发表在ACS Infectious Diseases期刊上，论文标题为“Sec61 Inhibitor Apratoxin S4 Potently Inhibits SARS-CoV-2 and Exhibits Broad-Spectrum Antiviral Activity”。 尽管存在COVID-19疫苗，但一些接受过疫苗注射的人仍然患上了COVID-19，而世界上只有一小部分人口接种了疫苗。这意味着仍然需要治疗，现在有一些针对SARS-CoV-2的RNA聚合酶---它用来在人体细胞内制造更多的病毒自己的RNA。但是其中一些药物，如瑞德西韦（remdesivir），除非在非常早期阶段使用，否则不会起作用，而且可能需要注射。 图片来自ACS Infectious Diseases, 2022, doi:10.1021/acsinfecdis.2c00008。 在寻找治疗COVID-19的新方法的过程中，不同的团队已经重新审视了那些已知可以对抗其他疾病的药物，这种策略被称为药物“重新利用”。其中一种临床前阶段的化合物是apratoxin S4，它是一种基于海洋天然产物的分子，具有抗癌活性。以前的研究表明，apratoxin可以靶向一种叫做Sec61的人类蛋白，该蛋白可以确保某些蛋白发生正确糖基化和正确折叠。由于SARS-CoV-2没有自己的分子机器来做这件事，它们劫持了这个过程，迫使人体细胞制造功能性的病毒蛋白。Sec61对于甲型流感病毒、HIV和登革热病毒造成感染是必不可少的，因此论文通讯作者Hendrik Luesch及其同事们想知道apratoxin是否可以成为一种广泛有效的也可以对抗SARS-CoV-2的泛病毒药物。 在对暴露于SARS-CoV-2的猴子和人类细胞的测试中，这些作者发现，与瑞德西韦治疗相比，用apratoxin S4治疗减少了受感染的细胞数量。apratoxin S4也有效地抵抗甲型流感病毒、寨卡病毒、登革热病毒和西尼罗河病毒感染。进一步的测试显示，apratoxin S4没有阻止SARS-CoV-2进入细胞，但它减少了在细胞中产生和运输的病毒蛋白的数量，特别是刺突蛋白，并且它减少了病毒RNA的复制。通过电子显微镜，他们观察到apratoxin S4也在很大程度上阻止了新病毒的形成，而且在SARS-CoV-2暴露的猴子细胞中，许多囊泡中没有或只有很少的全新病毒颗粒。他们说，还需要开展更多的研究，但是这些结果表明，apratoxin S4和人类Sec61蛋白的其他抑制剂是作用广泛的抗病毒药物，可能有助于对抗未来的大流行病。（生物谷 Bioon.com） 参考资料： Marie O. Pohl et al. Sec61 Inhibitor Apratoxin S4 Potently Inhibits SARS-CoV‑2 and Exhibits Broad-Spectrum Antiviral Activity. ACS Infectious Diseases, 2022, doi:10.1021/acsinfecdis.2c00008.

Scientists report that apratoxin S4, an anticancer drug candidate that targets a human protein, can interfere with the replication of many viruses, including SARS-CoV-2 and influenza A, offering a possible pan-viral therapy. More than two years into the COVID-19 pandemic, people are realizing that the "new normal" will probably involve learning to co-exist with SARS-CoV-2. Some treatments are available, but with new variants emerging, researchers are looking toward new strategies. In ACS Infectious Diseases, scientists now report that apratoxin S4, an anticancer drug candidate that targets a human protein, can interfere with the replication of many viruses, including SARS-CoV-2 and influenza A, offering a possible pan-viral therapy. Although COVID-19 vaccines exist, some people who received the shots have still become sick with the disease, and only a fraction of the world's population is vaccinated. That means treatments are still needed, and a few are now available that target the virus's RNA polymerase -- the enzyme it uses to make more of its own RNA inside human cells. But some of these drugs, such as remdesivir, don't work unless given at very early stages and can require injections. In the hunt for new ways to treat COVID-19, various teams have revisited drugs that are already known to fight other diseases, a strategy called "repurposing." One such preclinical stage compound is apratoxin S4 (Apra S4), which is a molecule based on a natural product that has anti-cancer activity. Previous studies have shown that apratoxins can target a human protein called Sec61, which ensures that certain proteins are properly glycosylated and folded correctly. Since viruses don't have their own machinery to do this, they hijack the process and force human cells to make functional viral proteins. Sec61 is essential for the influenza A, HIV and dengue viruses to cause infection, so Hendrik Luesch and colleagues wondered if apratoxins could be a broadly effective, pan-viral medication that could also combat SARS-CoV-2. In tests with monkey and human cells exposed to SARS-CoV-2, the researchers found that treatment with Apra S4 reduced the number of infected cells compared with remdesivir treatment. The molecule was also effective against influenza A, Zika virus, dengue and West Nile virus infections. Further testing revealed that Apra S4 didn't prevent SARS-CoV-2 from entering cells, but it reduced the amount of viral protein that was produced and transported in cells, especially the spike protein, and it decreased viral RNA replication. With electron microscopy, the team observed that Apra S4 also largely blocked the formation of new viruses, with many vesicles in SARS-CoV-2-exposed monkey cells having no or very few brand-new viral particles in them. The researchers say more studies are needed, but these results suggest that Apra S4 and other inhibitors of the human Sec61 protein are broadly acting antivirals that could help in the fight against future pandemics. The authors acknowledge funding from the National Institutes of Health, the Debbie and Sylvia DeSantis Chair professorship, the Department of Defense, the Dengue Human Immunology Project Consortium, philanthropic donations, JPB Foundation, the Open Philanthropy Project and the Swiss National Science Foundation.