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Artemisia annua L. extracts inhibit the in vitro replication of SARS-CoV-2 and two of its variants

M.S. Nair, Y. Huang, D.A. Fidock, View ORCID ProfileS.J. Polyak, J. Wagoner, M.J. Towler, P.J. Weathers
doi: https://doi.org/10.1101/2021.01.08.425825
M.S. Nair
aAaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA
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Y. Huang
aAaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA
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D.A. Fidock
bDepartment of Microbiology and Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
cDivision of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
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S.J. Polyak
dDepartment of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, 98104
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  • ORCID record for S.J. Polyak
J. Wagoner
dDepartment of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, 98104
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M.J. Towler
eDepartment of Biology and Biotechnology, Worcester Polytechnic Institute, Worcester, MA 01609, USA
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P.J. Weathers
eDepartment of Biology and Biotechnology, Worcester Polytechnic Institute, Worcester, MA 01609, USA
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  • For correspondence: weathers@wpi.edu
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ABSTRACT

Ethnopharmacological relevance Artemisia annua L. has been used for millennia in Southeast Asia to treat “fever”. Many infectious microbial and viral diseases have been shown to respond to A. annua and communities around the world use the plant as a medicinal tea, especially for treating malaria.

Aim of the Study SARS-CoV-2 (the cause of Covid-19) globally has infected and killed millions of people. Because of the broad-spectrum antiviral activity of artemisinin that includes blockade of SARS-CoV-1, we queried whether A. annua suppressed SARS-CoV-2.

Materials and Methods Using Vero E6 and Calu-3 cells, we measured anti viral activity SARS-CoV-2 activity against fully infectious virusof dried leaf extracts of seven cultivars of A. annua sourced from four continents. IC50s were calculated and defined as (the concentrations that inhibited viral replication by 50%.) and CC50s (the concentrations that kill 50% of cells) were calculated.

Results Hot-water leaf extracts based on artemisinin, total flavonoids, or dry leaf mass showed antiviral activity with IC50 values of 0.1-8.7 μM, 0.01-0.14 μg, and 23.4-57.4 μg, respectively. Antiviral efficacy did not correlate with artemisinin or total flavonoid contents of the extracts. One dried leaf sample was >12 years old, yet the hot-water extract was still found to be active. The UK and South African variants, B1.1.7 and B1.351, were similarly inhibited. While all hot water extracts were effective, concentrations of artemisinin and total flavonoids varied by nearly 100-fold in the extracts. Artemisinin alone showed an estimated IC50 of about 70 μM, and the clinically used artemisinin derivatives artesunate, artemether, and dihydroartemisinin were ineffective or cytotoxic at elevated micromolar concentrations. In contrast, the antimalarial drug amodiaquine had an IC50 = 5.8 μM. Extracts had minimal effects on infection of Vero E6 or Calu-3 cells by a reporter virus pseudotyped by the SARS-CoV-2 spike protein. There was no cytotoxicity within an order of magnitude above the antiviral IC90 values.

Conclusions A. annua extracts inhibit SARS-CoV-2 infection, and the active component(s) in the extracts is likely something besides artemisinin or a combination of components that block virus infection at a step downstream of virus entry. Further studies will determine in vivo efficacy to assess whether A. annua might provide a cost-effective therapeutic to treat SARS-CoV-2 infections.

  • Amodiaquine

  • Artemisinin

  • Artesunate

  • Artemether

  • Deoxyartemisinin

  • Dihydroartemisinin

  • Artemisia annua is effective in stopping replication of SARS-CoV-2 including 2 new variants.

  • The anti-viral effect does not correlate to artemisinin, nor to the total flavonoid content.

  • The anti-viral mechanism does not appear to involve blockade virus entry into cell.

  • The plant offers two additional benefits: a decreased inflammatory response and blunting of fibrosis.

  • A. annua may provide a safe, low-cost alternative for treating patients infected with SARS-CoV-2.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Author email addresses: Manoj Nair, mn2947{at}cumc.columbia.edu, Yaoxing Huang, yh3253{at}cumc.columbia.edu, David Fidock, df2260{at}cumc.columbia.edu, Stephen Polyak, polyak{at}uw.edu, Jessica Wagoner, jw25{at}uw.edu, Melissa Towler, eeyore{at}wpi.edu, Pamela Weathers, weathers{at}wpi.edu

  • New data added to show efficacy against 2 new SARS-CoV-2 variants.

  • Abbreviations

    ACT
    artemisinin combination therapy
    ASAQ
    artesunate amodiaquine
    DLA
    dried leaf Artemisia
    DW
    dry weight
    EMEM
    Essential Minimal Eagle’s Medium
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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    Posted February 24, 2021.
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    Artemisia annua L. extracts inhibit the in vitro replication of SARS-CoV-2 and two of its variants
    M.S. Nair, Y. Huang, D.A. Fidock, S.J. Polyak, J. Wagoner, M.J. Towler, P.J. Weathers
    bioRxiv 2021.01.08.425825; doi: https://doi.org/10.1101/2021.01.08.425825
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    Artemisia annua L. extracts inhibit the in vitro replication of SARS-CoV-2 and two of its variants
    M.S. Nair, Y. Huang, D.A. Fidock, S.J. Polyak, J. Wagoner, M.J. Towler, P.J. Weathers
    bioRxiv 2021.01.08.425825; doi: https://doi.org/10.1101/2021.01.08.425825

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