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Therapeutic strategies to target the Ebola virus life cycle. ​

Literature Information ​

DOI10.1038/s41579-019-0233-2
PMID31341272
JournalNature reviews. Microbiology
Impact Factor103.3
JCR QuartileQ1
Publication Year2019
Times Cited81
KeywordsEbola virus, therapeutic strategies, viral life cycle, monoclonal antibodies, RNA synthesis inhibitors
Literature TypeJournal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Review
ISSN1740-1526
Pages593-606
Issue17(10)
AuthorsThomas Hoenen, Allison Groseth, Heinz Feldmann

TL;DR ​

In the wake of the Ebola virus disease epidemic in West Africa, this review highlights the urgent need for enhanced therapies against viral hemorrhagic fevers, focusing on promising compounds that disrupt the filovirus life cycle, including monoclonal antibodies and RNA synthesis inhibitors. By leveraging advances in 'omics' analyses and high-throughput screening, the study emphasizes the potential of targeting various stages of the virus life cycle for therapeutic intervention, thereby contributing to the development of better treatment strategies for emerging viral diseases.

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Ebola virus · therapeutic strategies · viral life cycle · monoclonal antibodies · RNA synthesis inhibitors

Abstract ​

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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Primary Questions Addressed ​

  1. What are the specific mechanisms by which monoclonal antibodies like ZMapp and mAb114 interfere with the Ebola virus life cycle?
  2. How do high-throughput screening technologies contribute to the identification of new therapeutic targets for Ebola virus?
  3. In what ways can targeting viral RNA synthesis enhance the effectiveness of existing treatments for Ebola virus infection?
  4. What challenges do researchers face when developing therapies that target different stages of the Ebola virus life cycle?
  5. How do emerging therapies for Ebola compare to those developed for other viral hemorrhagic fevers in terms of efficacy and safety?

Key Findings ​

1. Research Background and Objective: The Ebola virus disease (EVD) epidemic in West Africa highlighted the urgent need for effective therapeutic strategies against emerging viral diseases, particularly those caused by filoviruses like the Ebola virus. The objective of this review is to explore various therapeutic approaches that target different stages of the Ebola virus life cycle, leveraging advancements in our understanding of viral biology and the application of modern 'omics' technologies.

2. Main Methods and Findings: The review synthesizes findings from recent research that has utilized high-throughput screening technologies and 'omics' analyses to identify both viral and host factors involved in Ebola virus infection. The authors assess various promising therapeutic compounds that intervene in the Ebola virus life cycle. Notable interventions discussed include monoclonal antibodies such as ZMapp, mAb114, and REGN-EB3, which have shown efficacy in neutralizing the virus. Additionally, antiviral agents like remdesivir and TKM-Ebola, which inhibit viral RNA synthesis, are highlighted. The review categorizes potential therapeutic targets into several stages of the viral life cycle: entry, RNA synthesis, gene expression, morphogenesis, and budding, providing a comprehensive overview of intervention strategies.

3. Core Conclusions: The findings underscore the importance of targeting multiple aspects of the Ebola virus life cycle to develop effective therapies. The review concludes that while several compounds have shown promise, ongoing research is needed to optimize these interventions and explore new therapeutic avenues. The therapeutic landscape for EVD is evolving, with the potential for a multi-faceted approach to treatment that enhances patient outcomes and mitigates the severity of the disease.

4. Research Significance and Impact: This review is significant as it not only highlights the advancements made in Ebola virus research since the West African epidemic but also emphasizes the importance of preparedness for future outbreaks of viral hemorrhagic fevers. By identifying critical intervention points in the virus life cycle, the research can inform the development of effective treatments. Furthermore, the insights gained may have broader implications for other emerging viral diseases, reinforcing the need for a proactive approach to viral pandemic preparedness. The exploration of therapeutic strategies discussed in this review could significantly contribute to public health efforts and vaccine development, ultimately leading to better management of Ebola and similar viral threats.

References ​

  1. Neglected filoviruses. - Robin Burk;Laura Bollinger;Joshua C Johnson;Jiro Wada;Sheli R Radoshitzky;Gustavo Palacios;Sina Bavari;Peter B Jahrling;Jens H Kuhn - FEMS microbiology reviews (2016)
  2. Characterization of a filovirus (Měnglà virus) from Rousettus bats in China. - Xing-Lou Yang;Chee Wah Tan;Danielle E Anderson;Ren-Di Jiang;Bei Li;Wei Zhang;Yan Zhu;Xiao Fang Lim;Peng Zhou;Xiang-Ling Liu;Wuxiang Guan;Libiao Zhang;Shi-Yue Li;Yun-Zhi Zhang;Lin-Fa Wang;Zheng-Li Shi - Nature microbiology (2019)
  3. Filoviruses and bats. - Amy J Schuh;Brian R Amman;Jonathan S Towner - Microbiology Australia (2017)
  4. Ebola Virus Shedding and Transmission: Review of Current Evidence. - Pauline Vetter;William A Fischer;Manuel Schibler;Michael Jacobs;Daniel G Bausch;Laurent Kaiser - The Journal of infectious diseases (2016)
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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)
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Literatures Citing This Work ​

  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)

... (71 more literatures)

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