Homo-harringtonine (HHT) – A highly effective drug against coronaviruses and the potential for large-scale clinical applications

  1. Hai-Jun Wen
  2. Pei Lin
  3. Gong-Xun Zhong
  4. Zhi-Chao Xu
  5. Lei Shuai
  6. Zhi-Yuan Wen
  7. Chong Wang
  8. Xue Cao
  9. Wen-Bin He
  10. Jing Feng
  11. Qi-Chun Cai
  12. Hua-Juan Ma
  13. Si-Jin Wu
  14. Guo-Dong Wang
  15. Xue-Mei Lyu
  16. Feng-Liang Liu
  17. Yong-Tang Zheng
  18. Hui Zeng
  19. Xiong-Lei He
  20. Hualan Chen
  21. Fu-Jie Zhang
  22. Chung-I Wu

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Abstract

In the search for treatment schemes of COVID-19, we start by examining the general weakness of coronaviruses and then identify approved drugs attacking that weakness. The approach, if successful, should identify drugs with a specific mechanism that is at least as effective as the best drugs proposed and are ready for clinical trials. All coronaviruses translate their non-structural proteins (∼16) in concatenation, resulting in a very large super-protein. Homo-harringtonine (HHT), which has been approved for the treatment of leukemia, blocks protein elongation very effectively. Hence, HHT can repress the replication of many coronaviruses at the nano-molar concentration. In two mouse models, HHT clears SARS-CoV-2 in 3 days, especially by nasal dripping of 40 ug per day. We also use dogs to confirm the safety of HHT delivered by nebulization. The nebulization scheme could be ready for large-scale applications at the onset of the next epidemics. For the current COVID-19, a clinical trial has been approved by the Ditan hospital of Beijing but could not be implemented for want of patients. The protocol is available to qualified medical facilities.

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  1. ScreenIT

    SciScore for 10.1101/2021.04.16.440104: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIACUC: The protocols were approved by the Committee on the Ethics of Animal Experiments of the HVRI of CAAS or Institutional Committee for Animal Care and Biosafety at Kunming Institute of Zoology, Chinese Academy of Sciences, respectively.
    RandomizationAll animals used in this study were chosen randomly.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableMouse-adapted SARS-CoV-2/HRB26/human/2020/CHN (HRB26M, GISAID access no. EPI_ISL_459910) was obtained by serially passaging the HRB26 virus in 4–6-week-old female mice until passage 14 and was propagated in Vero E6 cells.
    Cell Line AuthenticationContamination: Mycoplasma testing was performed at regular intervals and no mycoplasma contamination was detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    After blocked with 1% bovine serum albumin (BSA), cells were stained with anti-PEDV (SADS-CoV, or PDCoV) N polyclonal antibody (Wen’ s Foodstuffs Group Co., Ltd, China) (1:1000) at 37°C for 1 h.
    anti-PEDV
    suggested: None
    Cells were then washed with 1 × PBS and incubated with fluoresceinisothiocyanate (FITC) (1:500) or Cy3-labeled goat anti-mouse secondary antibody (KPL, USA) (1:500) at 37°C for 1 h.
    anti-mouse
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Infectious virus titers were determined by using a plaque forming unit (PFU) assay in Vero E6 cells.
    Vero E6
    suggested: RRID:CVCL_XD71)
    Confluent Vero or IPEC-J2 cell monolayers in 12-well plate were inoculated with various concentrations of HHT (1-1000nM) or the control normal DMEM for 1 h, followed by infection with PEDV, SADS-CoV, or PDCoV at an MOI of 0.1 or 0.01 for 1 h, and then the viral inoculums was removed and fresh maintenance medium containing different concentrations of HHT was added.
    Vero
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    In vivo antiviral studies of HHT at HVRI in Harbin: The mice for this study, 6-week-old female BALB/c, were obtained from Beijing Charles River Labs (Beijing, China).
    BALB/c
    suggested: RRID:IMSR_ORNL:BALB/cRl)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2021.04.16.440104v1 on bioRxiv