Abstract

Artemisia annua and its phytocompounds have a rich history in the research and treatment of malaria, rheumatoid arthritis, systemic lupus erythematosus, and other diseases. Currently, the World Health Organization recommends artemisinin-based combination therapy as the first-line treatment for multi-drug-resistant malaria. Due to the various research articles on the use of antimalarial drugs to treat coronaviruses, a question is raised: would A. annua and its compounds provide anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) properties? PubMed/MEDLINE, Scopus, and Google Scholar were searched for peer-reviewed articles that investigated the antiviral effects and mechanisms of A. annua and its phytochemicals against SARS-CoVs. Particularly, articles that evidenced the herb’s role in inhibiting the coronavirus-host proteins were favored. Nineteen studies were retrieved. From these, fourteen in silico molecular docking studies demonstrated potential inhibitory properties of artemisinins against coronavirus-host proteins including 3CLPRO, S protein, N protein, E protein, cathepsin-L, helicase protein, nonstructural protein 3 (nsp3), nsp10, nsp14, nsp15, and glucose-regulated protein 78 receptor. Collectively, A. annua constituents may impede the SARS-CoV-2 attachment, membrane fusion, internalization into the host cells, and hinder the viral replication and transcription process. This is the first comprehensive overview of the application of compounds from A. annua against SARS-CoV-2/coronavirus disease 2019 (COVID-19) describing all target proteins. A. annua’s biological properties, the signaling pathways implicated in the COVID-19, and the advantages and disadvantages for repurposing A. annua compounds are discussed. The combination of A. annua’s biological properties, action on different signaling pathways and target proteins, and a multi-drug combined-therapy approach may synergistically inhibit SARS-CoV-2 and assist in the COVID-19 treatment. Also, A. annua may modulate the host immune response to better fight the infection.

5. Conclusion

A. annua and its phytocompounds may be able to inhibit the SARS-CoV-2/host proteins 3CLPRO, S protein, CTSL, N protein, E protein, helicase protein, nsp3, nsp10, nsp14, nsp15, and GRP78 receptor. Thus, collectively, the A. annua constituents may impede the SARS-CoV-2 attachment, membrane fusion, internalization into the host cell, and hinder the viral replication and transcription process. The best inhibitions were attained by the interactions of artesunate-3CLPRO (−8.0 kcal/mol), artemisinin-3CLPRO (−8.06 kcal/mol), artemether-N protein (−8.0 kcal/mol), artesunate-N protein (−8.8 kcal/mol), artesunate-nsp3 (−8.1 kcal/mol), artesunate-nsp14 (−8.4 kcal/mol), and artesunate-nsp15 (−8.2 kcal/mol). Other appreciable scores of ≤ −7.0 kcal/mol were also reported ( Table 1 /Fig. 1 ). To date, no peer-reviewed articles confirmed a significant binding of A. annua and its compounds directly with RdRp, PLPRO, hACE-2 receptor, S/ACE-2 complex, 3a protein, or additional non-structural proteins that are important for the coronavirus replication. Nonetheless, the research on the SARS-CoV-2/COVID-19 is emerging rapidly with new peer-reviewed papers being published weekly, and other yet unknown target proteins may be involved. Not only the binding strength of an herb-compound to the viral proteins is important, but also the type of bond, fit, and stability should be considered when electing anti-SARS-CoV-2 options. However, the in vitro and in silico studies alone are not enough to determine the best antiviral candidates, and other factors need to be considered. Although in some studies the artemisinins did not show the highest binding capacity, the combination of their antiviral action, target-protein inhibition, and biological properties may synergistically contribute to the treatment of SARS-CoV-2 and intervene in additional signaling pathways to favorably influence the COVID-19 pathogenesis. Importantly, A. annua may re-modulate the host’s innate and adaptive immune system and assist in reducing the cytokine storm, ARDS, and COVID-19 symptoms. Advantages for repurposing artemisinins include low toxicity, safer higher dosages, few side-effects, cost-effectiveness, easy production, pre-existing pharmacokinetic and pharmacodynamic studies showing good profiles, well-understood modes of administration, drug sensitization to design drug and/or herbal-combination therapies, reduction of drug resistance (when drugs are associated), and dosage predictability based on other disease protocols. The evidence reviewed here supports future research and clinical trials to further understand the use of A. annua for the SARS-CoV-2 infection, COVID19 prevention, reduction of severity, treatment of different phases of the disease, and management of symptoms.