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Therapeutic strategies to target the Ebola virus life cycle. ​

文献信息 ​

DOI10.1038/s41579-019-0233-2
PMID31341272
期刊Nature reviews. Microbiology
影响因子103.3
JCR 分区Q1
发表年份2019
被引次数81
关键词埃博拉病毒, 治疗策略, 病毒生命周期, 单克隆抗体, RNA合成抑制剂
文献类型Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Review
ISSN1740-1526
页码593-606
期号17(10)
作者Thomas Hoenen, Allison Groseth, Heinz Feldmann

一句话小结 ​

本综述探讨了针对埃博拉病毒及其他丝状病毒的治疗方法，强调了通过对病毒生命周期的深入理解与高通量筛选技术的应用，识别潜在干预靶点的重要性。研究指出了多种有前景的化合物，包括单克隆抗体和抑制病毒RNA合成的药物，旨在为改善病毒性出血热的治疗提供新的思路。

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埃博拉病毒 · 治疗策略 · 病毒生命周期 · 单克隆抗体 · RNA合成抑制剂

摘要 ​

在西非埃博拉病毒病疫情之后，人们对改善新兴疾病治疗方法的需求有了更高的认识，包括由埃博拉病毒和其他丝状病毒引起的病毒性出血热。我们对病毒生命周期的不断深入理解，加上“组学”分析和高通量筛选技术的日益普及，增强了我们识别潜在病毒和宿主因素以及感染过程中可能作为干预靶点的各个方面的能力。在本综述中，我们讨论了在干扰丝状病毒生命周期方面显示出不同程度前景的化合物，包括单克隆抗体如ZMapp、mAb114和REGN-EB3，以及抑制病毒RNA合成的药物如瑞德西韦和TKM-Ebola。此外，我们还讨论了针对病毒生命周期各个方面的潜在可能性，如进入过程、病毒RNA合成和基因表达，以及形态发生和出芽。

英文摘要 ​

Following the Ebola virus disease epidemic in west Africa, there has been increased awareness of the need for improved therapies for emerging diseases, including viral haemorrhagic fevers such as those caused by Ebola virus and other filoviruses. Our continually improving understanding of the virus life cycle coupled with the increased availability of 'omics' analyses and high-throughput screening technologies has enhanced our ability to identify potential viral and host factors and aspects involved in the infection process that might be intervention targets. In this Review we address compounds that have shown promise to various degrees in interfering with the filovirus life cycle, including monoclonal antibodies such as ZMapp, mAb114 and REGN-EB3 and inhibitors of viral RNA synthesis such as remdesivir and TKM-Ebola. Furthermore, we discuss the general potential of targeting aspects of the virus life cycle such as the entry process, viral RNA synthesis and gene expression, as well as morphogenesis and budding.

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主要研究问题 ​

  1. 针对埃博拉病毒生命周期的不同阶段，哪些具体的干预策略最为有效？
  2. 除了单克隆抗体和RNA合成抑制剂外，还有哪些新兴的治疗方法可以考虑？
  3. 在开发针对埃博拉病毒的治疗策略时，如何平衡疗效与安全性？
  4. 未来的研究方向应该集中在哪些方面，以进一步改善对埃博拉病毒的治疗？
  5. 针对埃博拉病毒的治疗策略在其他病毒性出血热的应用前景如何？

核心洞察 ​

1. 研究背景和目的 ​

在西非爆发的埃博拉病毒病疫情之后，公众和科学界对新兴疾病的治疗需求有了更强烈的意识，尤其是针对埃博拉病毒及其他丝状病毒引起的病毒性出血热。研究的目的是通过提高对埃博拉病毒生命周期的理解，结合“组学”分析和高通量筛选技术，识别可能的病毒和宿主因子，从而为干预感染过程提供新的治疗靶点。

2. 主要方法和发现 ​

本文综述了多种已显示出在干扰丝状病毒生命周期方面具有潜力的化合物。包括单克隆抗体（如ZMapp、mAb114和REGN-EB3）和病毒RNA合成抑制剂（如remdesivir和TKM-Ebola）。通过对病毒生命周期不同阶段的研究，重点关注了病毒的进入过程、RNA合成与基因表达、形态发生及出芽等方面，以确定潜在的干预策略。

3. 核心结论 ​

研究表明，针对埃博拉病毒生命周期的各个环节开展干预有望为治疗提供新的方案。特别是单克隆抗体和RNA合成抑制剂在临床试验中显示出较好的疗效，表明通过靶向这些关键步骤可以有效抑制病毒复制和传播。此外，结合现代“组学”技术的应用，将更全面地揭示感染机制，为药物开发提供更精准的靶点。

4. 研究意义和影响 ​

本研究的意义在于为埃博拉病毒及其他丝状病毒的治疗策略提供了系统性的见解，强调了基础研究与临床应用的结合。通过明确病毒生命周期中的关键靶点，能够推动新药的开发并提高应对未来疫情的能力。此外，研究成果也为其他新兴病毒性疾病的治疗策略提供了借鉴，推动公共卫生领域的进步，增强全球应对病毒性出血热的能力。

参考文献 ​

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  3. Filoviruses and bats. - Amy J Schuh;Brian R Amman;Jonathan S Towner - Microbiology Australia (2017)
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  6. Serological Evidence for the Circulation of Ebolaviruses in Pigs From Sierra Leone. - Kerstin Fischer;Juliet Jabaty;Roland Suluku;Thomas Strecker;Allison Groseth;Sarah K Fehling;Anne Balkema-Buschmann;Bashiru Koroma;Kristina M Schmidt;Christine Atherstone;Hana M Weingartl;Thomas C Mettenleiter;Martin H Groschup;Thomas Hoenen;Sandra Diederich - The Journal of infectious diseases (2018)
  7. Ebola virus: unravelling pathogenesis to combat a deadly disease. - Thomas Hoenen;Allison Groseth;Darryl Falzarano;Heinz Feldmann - Trends in molecular medicine (2006)
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  9. The Pathogenesis of Ebola Virus Disease. - Laura Baseler;Daniel S Chertow;Karl M Johnson;Heinz Feldmann;David M Morens - Annual review of pathology (2017)
  10. Filovirus pathogenesis and immune evasion: insights from Ebola virus and Marburg virus. - Ilhem Messaoudi;Gaya K Amarasinghe;Christopher F Basler - Nature reviews. Microbiology (2015)

引用本文的文献 ​

  1. Ebola Virus in the Democratic Republic of the Congo: Advances and Remaining Obstacles in Epidemic Control, Clinical Care, and Biomedical Research. - Julie Erb-Alvarez;Aaron M Wendelboe;Daniel S Chertow - Chest (2020)
  2. Analysis of Resistance of Ebola Virus Glycoprotein-Driven Entry Against MDL28170, An Inhibitor of Cysteine Cathepsins. - Markus Hoffmann;Svenja Victoria Kaufmann;Carina Fischer;Wiebke Maurer;Anna-Sophie Moldenhauer;Stefan Pöhlmann - Pathogens (Basel, Switzerland) (2019)
  3. The Roles of Ebola Virus Soluble Glycoprotein in Replication, Pathogenesis, and Countermeasure Development. - Wenjun Zhu;Logan Banadyga;Karla Emeterio;Gary Wong;Xiangguo Qiu - Viruses (2019)
  4. Ebola Virus Uptake into Polarized Cells from the Apical Surface. - Meng Hu;Fei Wang;Wei Li;Xiaowei Zhang;Zhiping Zhang;Xian-En Zhang;Zongqiang Cui - Viruses (2019)
  5. Hexamer phasing governs transcription initiation in the 3'-leader of Ebola virus. - Simone Bach;Nadine Biedenkopf;Arnold Grünweller;Stephan Becker;Roland K Hartmann - RNA (New York, N.Y.) (2020)
  6. Potent neutralizing monoclonal antibodies against Ebola virus isolated from vaccinated donors. - Pengfei Fan;Xiangyang Chi;Guodong Liu;Guanying Zhang;Zhengshan Chen;Yujiao Liu;Ting Fang;Jianmin Li;Logan Banadyga;Shihua He;Changming Yu;Xiangguo Qiu;Wei Chen - mAbs (2020)
  7. Review of Emerging Pharmacotherapy for the Treatment of Coronavirus Disease 2019. - Ashley Barlow;Kaitlin M Landolf;Brooke Barlow;Siu Yan Amy Yeung;Jason J Heavner;Cassidy W Claassen;Mojdeh S Heavner - Pharmacotherapy (2020)
  8. Quantification of Viral and Host Biomarkers in the Liver of Rhesus Macaques: A Longitudinal Study of Zaire Ebolavirus Strain Kikwit (EBOV/Kik). - Alexandra Greenberg;Bertrand R Huber;David X Liu;James P Logue;Amanda M W Hischak;Randy J Hart;Maureen Abbott;Nejra Isic;Yohei M Hisada;Nigel Mackman;Richard S Bennett;Lisa E Hensley;John H Connor;Nicholas A Crossland - The American journal of pathology (2020)
  9. Viral genomics in Ebola virus research. - Nicholas Di Paola;Mariano Sanchez-Lockhart;Xiankun Zeng;Jens H Kuhn;Gustavo Palacios - Nature reviews. Microbiology (2020)
  10. A Conserved Tryptophan in the Ebola Virus Matrix Protein C-Terminal Domain Is Required for Efficient Virus-Like Particle Formation. - Kristen A Johnson;Rudramani Pokhrel;Melissa R Budicini;Bernard S Gerstman;Prem P Chapagain;Robert V Stahelin - Pathogens (Basel, Switzerland) (2020)

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