Home
JournalsCollections
For Authors For Reviewers For Editorial Board Members
Article Processing Charges Open Access
Ethics Advertising Policy
Editorial Policy Resource Center
Company Information Contact Us
Publications > Journals > Journal of Exploratory Research in Pharmacology> Article Full Text
Review Article
OPEN ACCESS

Download PDF

Artemisia annua L. and Its Derivatives: Their Antiviral Effects on COVID-19 and Possible Mechanisms

  • Iftekhar Ahmad1,* ,
  • Rahman Ali2,
  • Monyck Jeane dos Santos Lopes3,
  • Carl Hermann Dino Steinmetz4 and
  • Faiz Ul Haq1
Journal of Exploratory Research in Pharmacology   2022;7(1):54-58

doi: 10.14218/JERP.2021.00034

Received:

Revised:

Accepted:

Published online:

 Author information

Citation: Ahmad I, Ali R, dos Santos Lopes MJ, Steinmetz CHD, Haq FU. Artemisia annua L. and Its Derivatives: Their Antiviral Effects on COVID-19 and Possible Mechanisms. J Explor Res Pharmacol. 2022;7(1):54-58. doi: 10.14218/JERP.2021.00034.

Abstract

COVID-19 is a worldwide pandemic. Currently, there are a few approved effective antiviral drugs against COVID-19. Therefore, an effective way to treat an emerging disease is to use existing medicines, which usually have a safety profile. A large number of compounds are produced from traditional medicinal plants and some of them that have antiviral activity could be used as therapeutics, such as Artemisia annua L (A. annua L.). Here, we update the information on the therapeutic effects and possible antiviral mechanisms of A. annua L. and their derivatives against severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection will be updated. The A. annua L. derivatives might be effective alternatives for COVID-19 treatment. A. annua L. might act against the SARS-CoV-2 infection by inhibiting its invasion, angiotensin-converting enzyme2, cluster of differentiation 147, and transmembrane protease serine 2 expression, virus replication, reducing oxidative stress and inflammation by attenuating Nrf2 and NF-kB signaling, and mitigating lung damage in patients with COVID-19. However, clinical effectiveness needs to be demonstrated.

Keywords

Coronavirus, Drug discovery, Phytocompounds, Pharmacological action, SARS-CoV-2

Introduction

In December 2019, a cluster of pneumonia cases emerged that was associated with a novel coronavirus (2019-nCoV) in Wuhan city, Hubei Province, China.1 Based on a phylogenetic and genetic analysis of the viral taxonomy, the novel coronavirus 2019 was designated as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2 or Coronavirus-19), which caused coronavirus disease 2019 (COVID-19).2 Until September, 2021, SARS-CoV-2 infection resulted in >224 million laboratory-confirmed cases with approximately 4 million deaths worldwide. Currently, limited antiviral drugs have been approved to treat SARS-coronavirus-2 infection although different types of vaccines are now available to prevent severe COVID-19 disease in humans.3 Because COVID-19 has caused several waves of disease and severely affects social lives, an effective antiviral agent is needed to combat the current pandemic.

Clinically, there are a few antiviral drugs, anti-inflammatory medicines, and supportive therapies available to treat COVID-19 patients. For treatment and prophylaxis of the viral infection, the drug should be adequate, safe, and low cost.4,5 Artemisinin is a safe drug in the clinic. Artemisia and their derivatives have an excellent safety profile, low toxicity and adverse effects are relatively cheap, and are easily produced. In addition, these drugs have excellent pharmacokinetic and pharmacodynamic characteristics. Artemisinin can be used in combination with other drugs to increase therapeutic effectiveness and delay the development of drug resistance.6,7 The discovery and marketing of new antiviral agents often take a long time (e.g., months to years). Therefore, an effective strategy to treat an emerging disease could be to repurpose clinically available medicines, which usually have a safety profile.

Artemisia annua L. is easily obtained and has a long history and safety record in the treatment of hyperlipidemia, malarial, plasmodial, and inflammatory diseases. Furthermore, A. annua L. has anticonvulsant, antiviral, antimicrobial, and anticholesterol activities.4,8 Traditionally, artesunate (a derivative of artemisinin) has been used for the treatment of malaria and viral diseases.8,9 Recently, a clinical study indicated that treatment with artesunate could significantly shorten the duration of the hospital stay and reduce the symptoms in COVID-19 patients in China.10

Chemically, A. annua L. contains sterols, terpenes, flavonoids, phenolics, and polysaccharides.8,11 Artemisinin is a bioactive component that is extracted from A. annua L., has high efficiency and low toxicity, and is approved by the Food and Drug Administration9,12 and the World Health Organization (WHO) for the control of malaria.13,14 Artemisinin and other compounds from A. annua L. have been used in the management of several types of diseases, including autoimmune diseases, diabetes, cancer, parasitosis, viral infections, and atherosclerosis.4,8,9,12 The methanolic extracts from A. annua L. might be valuable for antiviral therapy, because they have higher activity against the Herpes Simplex virus type-1 than acyclovir.12 The ethanolic extracts of A. annua L. have significant antiviral activity against SARS-coronavirus with a 50% cytotoxic concentration (CC50) of 1,053 ± 92.8 µg/mL and 50% effective concentration (EC50) of 34.5 ± 2.6 µg/mL. These observations suggest that A. annua L. might be valuable for the treatment of COVID-19.15 In addition, A. annua L. might have potent inhibitory activities against the Epstein-Barr Virus, Cytomegalovirus, Herpes Simplex Virus 1, Human Herpes Virus 6A, and Human Papillomavirus.8

Molecular modeling was used to show that phytocompounds of artemisinin could bind to COVID-19.16 Furthermore, A. annua L. has potent anti-inflammatory activity that might inhibit or reduce inflammation and lung injury in COVID-19 patients.17 In the current article, the possible mechanisms underlying the actions of A. annua L. against SARS-CoV-2 will be highlighted.

Antiviral activities of A. annua L. derivatives against SARS-CoV-2

SARS-CoV-2 is a positive-sense single-stranded RNA virus; its structural proteins have a spike, envelope, membrane, and nucleocapsid; and SARS-CoV-2 contains the largest gene, the ORF1ab, coding the pp1ab protein and 15 nsps.18 SARS-CoV-2 can interact with the cluster of differentiation 147 (CD147) and angiotensin-converting enzyme-2 (ACE-2) on host cells for invasion.18,19 Drugs that interfere with ACE2, CD147 expression and spike proteins and their structures might inhibit viral entry, subsequent replication, and dissemination among other cells, mitigating COVID-19 disease.19 It is well known that A. annua L. contains active compounds that have antiviral activities, such as artemisinin, arteannuin B, artemisinic acid, quinic acid, caffeic acid, quercetin, rutin, and crysosplenetin.8 Artemisinin and artesunate can inhibit the replication of the Hepatitis C Virus, which, similar to the SARS-CoV-2 virus, is a positive-sense single-stranded RNA virus.13 In addition, Artesunate can inhibit cytomegalovirus20 and JC polyomavirus replication.13

A. annua L. can inhibit SARS-CoV-2 viral invasion and replication, and reduce oxidative stress, consequently reducing inflammation during COVID-19 (Fig. 1). The following route might provide a critical target for the development of effective antiviral agents. The pharmacological mechanisms of A. annua L. and their compounds might lead to the development of potential antiviral agents against COVID-19.

<italic>Artemisia annua</italic> L. and their derivatives against SARS-CoV-2 infection.
Fig. 1  Artemisia annua L. and their derivatives against SARS-CoV-2 infection.

A. annua L. derivatives could fight against SARS-CoV-2 by inhibiting entry, ACE2, CD147, TMPRSS2, and S expression into host cells; reducing virus replication by inhibiting 3CLpro. A. annua L. derivatives can reduce oxidative stress by increasing Nrf2 expression, and inhibit the NF-κB signaling, limiting pro-inflammatory cytokine production, cytokine storm, inflammation, lung damage, and fatal inflammation that are caused by SARS-CoV-2. 3CLpro, 3-chymotrypsin-like protease; ACE2, angiotensin-converting enzyme2; CD147, cluster of differentiation 147; TMPRSS2, transmembrane protease serine 2.

A. annua L. against SARS-CoV-2 invasion: ACE-2, TMPRSS2, CD147, and S

In host cells, ACE2, CD147, and extracellular matrix metalloproteinase inducer (EMMPRIN) are receptors for SARS-CoV-2.18,19,21 The spike glycoprotein (S) of SARS-CoV-2 can bind to the ACE2 or CD147 on the host cell, and enter the cell, where the virus replicates and spreads to other cells.19,22 The decrease in ACE2 and CD147 expression might be protective against COVID-19.19,22

During virus entry into cells, SARS-CoV-2 requires cellular proteases, such as trypsin-like protease cathepsins, and transmembrane protease serine 2 (TMPRSS2) that cleaves the S protein to promote fusion of the human and viral cellular membranes.18,23,24 Therefore, a decrease in the activity of these enzymes might be important for the control of SARS-CoV-2 infection.

Of interest, a previous study reported that androgens can upregulate the expression of TMPRSS2 protein and ACE2.25 Artemisinin can induce androgen receptor degradation via the 26S proteasome and disrupt the androgen response.26 Therefore, Artemisinin might inhibit SARS-CoV-2 infection by limiting the expression of ACE-2 and TMPRSS2 in sensitive cells (Fig. 1).18

CD147 is a transmembrane glycoprotein encoded by the Basigin gene in humans. CD147 can increase the synthesis of matrix metalloproteinases (MMPs) and pro-inflammatory cytokines.14 CD147 and MMPs expression can be enhanced by protein kinase (PK) and mitogen-activated protein kinase (MAPK) signaling.14 Artemisinin at 20–80 µg/mL inhibited the expression of CD147 in human cells. In addition, artemisinin strongly blocked PMA-induced CD147 expression by attenuating PKCδ and MAPK phosphorylation in human monocytes.14 Artesunate inhibited human cytomegalovirus replication by reducing PK activity.27 Therefore, artemisinin might be effective in the control of SARS-CoV-2 infections.

A. annua L. against SARS-CoV-2 replication: 3CLpro

The conserved 3-chymotrypsin-like protease (3CLpro) or main protease (Mpro), controls coronavirus transcription and virus replication. Their inhibition can reduce virus replication. A recent study showed that A. annua L. could inhibit the enzymatic activity of 3CLpro that is produced by SARS-CoV-2 during COVID-19 infection, which inhibits COVID-19 replication.17

A. annua L. against SARS-CoV-2 infection: Nrf2 and NF-kB

Nrf2 is a transcription factor and can regulate the cellular antioxidant response. Nrf2 signaling can reduce oxidative stress, which contributes to disease progression.28 In addition, Nrf2 can attenuate pulmonary fibrosis by upregulating antioxidant expression and defense enzymes.29 Enhanced oxidative stress is associated with pulmonary fibrosis and acute respiratory distress syndrome. Of note, pulmonary fibrosis contributes to the progression of COVID-19, which leads to high mortality in COVID-19 patients.30 Hence, modulation of Nrf2 activity might be valuable for the control of COVID-19 related pulmonary fibrosis.

A. annua L. can activate Nrf2 signaling that suppresses oxidative stress and inflammation.28,31A. annua L. has potent antioxidant activity and high phenolic content.32 Artesunate, an A. annua L. derivative, is a promising agent that could improve lung fibrosis by inhibiting the activity of profibrotic molecules.33 Artemisinin, which is a derivative of A. annua L., is an Nrf2 activator and has antioxidant and anti-inflammatory effects. Treatment with artemisinin inhibits bleomycin-induced lung damage in wild-type mice.28 Mechanistically, artemisinin can activate and stabilize Nrf2 by reducing its ubiquitination and degradation. An A. annua L. medicinal approach that targets Nrf-2 might offer antioxidant activity for humans against tissue damage and antifibrotic activity against SARS-CoV-2 infection and confer protection against tissue damage in other organs.

NF-κB is a protein complex that regulates gene transcription, cell survival, and stimulates pro-inflammatory cytokine productions.34 NF-κB signaling contributes to the pathogenesis of lung disease, including Acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome, and respiratory viral infections.13,34 The increase in cytokine production results in a cytokine storm and leads to the accumulation of fluid in the air sacs of alveoli, which causes suffocation.22 During COVID-19, severe disease can induce a cytokine storm, and cause fatal inflammation, leading to multiple organ dysfunction syndromes.13,22 Therefore, the inhibition of NF-κB signaling might be valuable in the control of COVID-19.13,22

Artesunate is an A. annua L. derivate and can inhibit NF-κB signaling, limiting virus replication. Artesunate has been demonstrated to inhibit chloroquine-like endocytosis, which might be effective for the treatment of SARS-CoV-2 infection.13 Therefore, artesunate might inhibit NF-κB signaling during SARS-CoV-2 infection to attenuate the cytokine storm. Artesunate might have the anti-inflammatory activity to reduce the inflammatory response, pro-inflammatory cytokine production, and lung inflammation that is caused by SARS-CoV-2 infection.

Future directions

The methanolic extracts of A. annua L. might be an appropriate candidate for antiviral therapy, because they have the highest antiviral potential against other viral replication. Furthermore, A. annua L. has shown preclinically that it has potent activities against SARS-CoV-2 infection and might be important for the control of COVID-19. However, the therapeutic efficacy and safety of these potential medicines for the treatment of COVID-19 need to be tested in clinical trials.

Conclusions

Repurposing drugs is an effective strategy to discover a therapeutic agent for the treatment of COVID-19. The A. annua L. derivatives might be potential candidates in COVID-19 treatment. A. annua L. can fight against SARS-CoV-2 infection by inhibiting its entry, ACE2, CD147, TMPRSS2, and S expression in host cells and reducing its replication by inhibiting 3CLpro. Furthermore, A. annua L. derivatives can reduce oxidative stress by increasing Nrf2 activity, inhibiting NF-κB signaling, reducing pro-inflammatory cytokine production, cytokine storm, inflammation, lung damage, and fatal inflammation that is caused by SARS-CoV-2. Their therapeutic efficacy and safety in the treatment of COVID-19 patients in clinical trials are urgently required.

Abbreviations

3CLpro: 

3-chymotrypsin-like protease

ACE-2: 

angiotensin-converting enzyme-2

BSG: 

Basigin

CC: 

cytotoxic concentration

CD147: 

cluster of differentiation 147

COVID-19: 

coronavirus disease

EC: 

effective concentration

EMMPRIN: 

extracellular matrix metalloproteinase inducer

FDA: 

Food and Drug Administration

MAPK: 

mitogen-activated protein kinase

MMPs: 

matrix metalloproteinases

Mpro: 

main protease

PK: 

protein kinase

SARS: 

severe acute respiratory syndrome coronavirus

TMPRSS2: 

transmembrane protease serine 2

Declarations

Acknowledgement

We thank all our friends and respected teachers for their help. Our sincere thanks to all the health care workers in the frontline of COVID-19 treatment.

Funding

None.

Conflict of interest

The authors have no conflicts of interest related to this publication.

Authors’ contributions

IA and FUH contributed to the study concept and design, ML and CHS performed data analysis, IA and RA drafted the manuscript, ML and FUH critically revised the manuscript.

References

  1. Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 2020;395(10223):514-523 View Article PubMed/NCBI
  2. Jiang S, Shi Z, Shu Y, Song J, Gao GF, Tan W, et al. A distinct name is needed for the new coronavirus. Lancet 2020;395(10228):949 View Article PubMed/NCBI
  3. Machingaidze S, Wiysonge CS. Understanding COVID-19 vaccine hesitancy. Nat Med 2021;27(8):1338-1339 View Article PubMed/NCBI
  4. Haq FU, Roman M, Ahmad K, Rahman SU, Shah SMA, Suleman N, et al. Artemisia annua: Trials are needed for COVID-19. Phytother Res 2020;34(10):2423-2424 View Article PubMed/NCBI
  5. Mhatre S, Srivastava T, Naik S, Patravale V. Antiviral activity of green tea and black tea polyphenols in prophylaxis and treatment of COVID-19: A review. Phytomedicine 2021;85:153286 View Article PubMed/NCBI
  6. Cheong DHJ, Tan DWS, Wong FWS, Tran T. Anti-malarial drug, artemisinin and its derivatives for the treatment of respiratory diseases. Pharmacol Res 2020;158:104901 View Article PubMed/NCBI
  7. Fuzimoto AD. An overview of the anti-SARS-CoV-2 properties of Artemisia annua, its antiviral action, protein-associated mechanisms, and repurposing for COVID-19 treatment. J Integr Med 2021;19(5):375-388 View Article PubMed/NCBI
  8. Septembre-Malaterre A, Lalarizo Rakoto M, Marodon C, Bedoui Y, Nakab J, Simon E, et al. Artemisia annua, a traditional plant brought to light. Int J Mol Sci 2020;21(14):4986 View Article PubMed/NCBI
  9. Zeng Z, Xu J, Zheng W. Artemisinin protects PC12 cells against β-amyloid-induced apoptosis through activation of the ERK1/2 signaling pathway. Redox Biol 2017;12:625-633 View Article PubMed/NCBI
  10. Kapepula PM, Kabengele JK, Kingombe M, Van Bambeke F, Tulkens PM, Sadiki Kishabongo A, et al. Artemisia spp. derivatives for COVID-19 treatment: Anecdotal use, political hype, treatment potential, challenges, and road map to randomized clinical trials. Am J Trop Med Hyg 2020;103(3):960-964 View Article PubMed/NCBI
  11. Khan MAAA, Jain DC, Bhakuni RS, Zaim M, Thakur RS. Occurrence of some antiviral sterols in Artemisia annua. Plant Sci 1991;75(2):161-165 View Article PubMed/NCBI
  12. Karamoddini M, Emami S, Ghannad M, Sani E, Sahebkar A. Antiviral activities of aerial subsets of Artemisia species against Herpes Simplex virus type 1 (HSV1) in vitro. Asian Biomedicine 2017;5(1):63-68 View Article PubMed/NCBI
  13. Uzun T, Toptas O. Artesunate: could be an alternative drug to chloroquine in COVID-19 treatment?. Chin Med 2020;15:54 View Article PubMed/NCBI
  14. Wang Y, Huang ZQ, Wang CQ, Wang LS, Meng S, Zhang YC, et al. Artemisinin inhibits extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase-9 expression via a protein kinase Cδ/p38/extracellular signal-regulated kinase pathway in phorbol myristate acetate-induced THP-1 macrophages. Clin Exp Pharmacol Physiol 2011;38(1):11-18 View Article PubMed/NCBI
  15. Li SY, Chen C, Zhang HQ, Guo HY, Wang H, Wang L, et al. Identification of natural compounds with antiviral activities against SARS-associated coronavirus. Antiviral Res 2005;67(1):18-23 View Article PubMed/NCBI
  16. Rolta R, Salaria D, Sharma P, Sharma B, Kumar V, Rathi B, et al. Phytocompounds of Rheum emodi, Thymus serpyllum, and Artemisia annua Inhibit Spike Protein of SARS-CoV-2 Binding to ACE2 Receptor: In Silico Approach. Curr Pharmacol Rep 2021;7:135-149 View Article PubMed/NCBI
  17. Law S, Leung AW, Xu C. Is the traditional Chinese herb “Artemisia annua” possible to fight against COVID-19?. Integr Med Res 2020;9(3):100474 View Article PubMed/NCBI
  18. Shereen MA, Khan S, Kazmi A, Bashir N, Siddique R. COVID-19 infection: Origin, transmission, and characteristics of human coronaviruses. J Adv Res 2020;24:91-98 View Article PubMed/NCBI
  19. Ulrich H, Pillat MM. CD147 as a target for COVID-19 treatment: suggested effects of azithromycin and stem cell engagement. Stem Cell Rev Rep 2020;16(3):434-440 View Article PubMed/NCBI
  20. Kaptein SJ, Efferth T, Leis M, Rechter S, Auerochs S, Kalmer M, et al. The anti-malaria drug artesunate inhibits replication of cytomegalovirus in vitro and in vivo. Antiviral Res 2006;69(2):60-69 View Article PubMed/NCBI
  21. Wang K, Chen W, Zhou YS, Lian JQ, Zhang Z, Du P, et al. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein. BioRxiv [Preprint] 2020:2020.03.14.988345 View Article PubMed/NCBI
  22. Elkhodary MSM. Treatment of COVID-19 by controlling the activity of the nuclear factor-Kappa B. CellBio 2020;9(2):109-121 View Article PubMed/NCBI
  23. Augustin Y, Staines H, Kamarulzaman A, Platteeuw H, Krishna S. Artesunate may attenuate the effects of Cytokine Release Syndrome (CRS) in Covid-19 disease by targeting Interleukin-6 and associated inflammatory response pathways. OSF Preprints 2020 View Article PubMed/NCBI
  24. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181(2):271-280.e8 View Article PubMed/NCBI
  25. Wambier CG, Goren A. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is likely to be androgen mediated. J Am Acad Dermatol 2020;83(1):308-309 View Article PubMed/NCBI
  26. Steely AM, Willoughby JA, Sundar SN, Aivaliotis VI, Firestone GL. Artemisinin disrupts androgen responsiveness of human prostate cancer cells by stimulating the 26S proteasome-mediated degradation of the androgen receptor protein. Anticancer Drugs 2017;28(9):1018-1031 View Article PubMed/NCBI
  27. Efferth T, Marschall M, Wang X, Huong SM, Hauber I, Olbrich A, et al. Antiviral activity of artesunate towards wild-type, recombinant, and ganciclovir-resistant human cytomegaloviruses. J Mol Med (Berl) 2002;80(4):233-242 View Article PubMed/NCBI
  28. Chen W, Li S, Li J, Zhou W, Wu S, Xu S, et al. Artemisitene activates the Nrf2-dependent antioxidant response and protects against bleomycin-induced lung injury. FASEB J 2016;30(7):2500-2510 View Article PubMed/NCBI
  29. Walters DM, Cho HY, Kleeberger SR. Oxidative stress and antioxidants in the pathogenesis of pulmonary fibrosis: a potential role for Nrf2. Antioxid Redox Signal 2008;10(2):321-332 View Article PubMed/NCBI
  30. George PM, Wells AU, Jenkins RG. Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. Lancet Respir Med 2020;8(8):807-815 View Article PubMed/NCBI
  31. Kim MH, Seo JY, Kim JS. Artemisia annua L. extract ameliorates galactose-induced cognitive impairment in mice. Food Sci Biotechnol 2015;24:1901-1905 View Article PubMed/NCBI
  32. Ferreira JF, Luthria DL, Sasaki T, Heyerick A. Flavonoids from Artemisia annua L. as antioxidants and their potential synergism with artemisinin against malaria and cancer. Molecules 2010;15(5):3135-3170 View Article PubMed/NCBI
  33. Wang C, Xuan X, Yao W, Huang G, Jin J. Anti-profibrotic effects of artesunate on bleomycin-induced pulmonary fibrosis in Sprague Dawley rats. Mol Med Rep 2015;12(1):1291-1297 View Article PubMed/NCBI
  34. Christman JW, Sadikot RT, Blackwell TS. The role of nuclear factor-kappa B in pulmonary diseases. Chest 2000;117(5):1482-1487 View Article PubMed/NCBI

Copyright © 2022 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • © 2024 Xia & He Publishing Inc.
  • Total visits : 2587917
  • Visits today : 280