{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T21:38:35Z","timestamp":1792618715896,"version":"4.5.0"},"reference-count":191,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T00:00:00Z","timestamp":1677110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institute of Health","doi-asserted-by":"publisher","award":["R15DK128757"],"award-info":[{"award-number":["R15DK128757"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institute of Health","doi-asserted-by":"publisher","award":["P20GM103429"],"award-info":[{"award-number":["P20GM103429"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"Arkansas IDeA Network of Biomedical Research Excellence\u2014Research and Development","doi-asserted-by":"publisher","award":["R15DK128757"],"award-info":[{"award-number":["R15DK128757"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"Arkansas IDeA Network of Biomedical Research Excellence\u2014Research and Development","doi-asserted-by":"publisher","award":["P20GM103429"],"award-info":[{"award-number":["P20GM103429"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had a profound impact on the world\u2019s health and economy. Although the end of the pandemic may come in 2023, it is generally believed that the virus will not be completely eradicated. Most likely, the disease will become an endemicity. The rapid development of vaccines of different types (mRNA, subunit protein, inactivated virus, etc.) and some other antiviral drugs (Remdesivir, Olumiant, Paxlovid, etc.) has provided effectiveness in reducing COVID-19\u2019s impact worldwide. However, the circulating SARS-CoV-2 virus has been constantly mutating with the emergence of multiple variants, which makes control of COVID-19 difficult. There is still a pressing need for developing more effective antiviral drugs to fight against the disease. Plants have provided a promising production platform for both bioactive chemical compounds (small molecules) and recombinant therapeutics (big molecules). Plants naturally produce a diverse range of bioactive compounds as secondary metabolites, such as alkaloids, terpenoids\/terpenes and polyphenols, which are a rich source of countless antiviral compounds. Plants can also be genetically engineered to produce valuable recombinant therapeutics. This molecular farming in plants has an unprecedented opportunity for developing vaccines, antibodies, and other biologics for pandemic diseases because of its potential advantages, such as low cost, safety, and high production volume. This review summarizes the latest advancements in plant-derived drugs used to combat COVID-19 and discusses the prospects and challenges of the plant-based production platform for antiviral agents.<\/jats:p>","DOI":"10.3390\/life13030617","type":"journal-article","created":{"date-parts":[[2023,2,23]],"date-time":"2023-02-23T03:56:58Z","timestamp":1677124618000},"page":"617","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Plants as Biofactories for Therapeutic Proteins and Antiviral Compounds to Combat COVID-19"],"prefix":"10.3390","volume":"13","author":[{"given":"Corbin","family":"England","sequence":"first","affiliation":[{"name":"Arkansas Biosciences Institute, Arkansas State University, Jonesboro, AR 72401, USA"},{"name":"Molecular Biosciences Program, Arkansas State University, Jonesboro, AR 72401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"TrejoMartinez","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Arkansas State University, Jonesboro, AR 72401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"PerezSanchez","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Arkansas State University, Jonesboro, AR 72401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uddhab","family":"Karki","sequence":"additional","affiliation":[{"name":"Arkansas Biosciences Institute, Arkansas State University, Jonesboro, AR 72401, USA"},{"name":"Molecular Biosciences Program, Arkansas State University, Jonesboro, AR 72401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0106-2516","authenticated-orcid":false,"given":"Jianfeng","family":"Xu","sequence":"additional","affiliation":[{"name":"Arkansas Biosciences Institute, Arkansas State University, Jonesboro, AR 72401, USA"},{"name":"College of Agriculture, Arkansas State University, Jonesboro, AR 72401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S0140-6736(20)30251-8","article-title":"Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding","volume":"395","author":"Lu","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41580-021-00418-x","article-title":"Mechanisms of SARS-CoV-2 entry into cells","volume":"23","author":"Jackson","year":"2022","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/s41586-020-2180-5","article-title":"Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor","volume":"581","author":"Lan","year":"2020","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Leung, K., Lau, E.H.Y., Wong, C.K.H., Leung, G.M., and Wu, J.T. (Nat. Med., 2023). Estimating the transmission dynamics of SARS-CoV-2 Omicron BF.7 in Beijing after the adjustment of zero-COVID policy in November\u2013December 2022, Nat. Med., ahead of print.","DOI":"10.1038\/s41591-023-02212-y"},{"key":"ref_5","first-page":"e7423","article-title":"Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2): An update","volume":"12","author":"Pal","year":"2020","journal-title":"Cureus"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1038\/s41401-020-0485-4","article-title":"Structural and functional properties of SARS-CoV-2 spike protein: Potential antivirus drug development for COVID-19","volume":"41","author":"Huang","year":"2020","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1007\/s00134-020-05985-9","article-title":"Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: Molecular mechanisms and potential therapeutic target","volume":"46","author":"Zhang","year":"2020","journal-title":"Intensive Care Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2070","DOI":"10.1038\/s41467-020-16048-4","article-title":"Neutralization of SARS-CoV-2 spike pseudotyped virus by recombinant ACE2-Ig","volume":"11","author":"Lei","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"701501","DOI":"10.3389\/fimmu.2021.701501","article-title":"SARS-CoV-2 vaccines based on the spike glycoprotein and implications of new viral variants","volume":"12","author":"Sampieri","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"eabc8413","DOI":"10.1126\/sciimmunol.abc8413","article-title":"The receptor binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients","volume":"5","author":"Premkumar","year":"2020","journal-title":"Sci. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Abduljaleel, Z., Shahzad, N., Aziz, S.A., and Malik, S.M. (Mol. Divers., 2022). Monoclonal antibody designed for SARS-nCoV-2 spike protein of receptor binding domain on antigenic targeted epitopes for inhibition to prevent viral entry, Mol. Divers., published online ahead of print.","DOI":"10.1007\/s11030-022-10449-x"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/s41586-021-04385-3","article-title":"Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies","volume":"602","author":"Cao","year":"2022","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1016\/S0140-6736(22)00941-2","article-title":"Risk of long COVID associated with delta versus omicron variants of SARS-CoV-2","volume":"399","author":"Antonelli","year":"2022","journal-title":"Lancet"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1015355","DOI":"10.3389\/fimmu.2022.1015355","article-title":"Oral GS-441524 derivatives: Next-generation inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase","volume":"13","author":"Wang","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1056\/NEJMc2214302","article-title":"Efficacy of antiviral agents against omicron subvariants BQ.1.1 and XBB. N","volume":"388","author":"Imai","year":"2023","journal-title":"Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1038\/s41590-022-01130-4","article-title":"Fighting the SARS-CoV-2 pandemic requires a global approach to understanding the heterogeneity of vaccine responses","volume":"23","author":"Tomalka","year":"2022","journal-title":"Nat. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1111\/all.15004","article-title":"A bird\u2019s eye view on the role of dendritic cells in SARS-CoV-2 infection: Perspectives for immune-based vaccines","volume":"77","author":"Galati","year":"2022","journal-title":"Allergy"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1002\/jmv.27517","article-title":"Broad-spectrum prodrugs with anti-SARS-CoV-2 activities: Strategies, benefits, and challenges","volume":"94","author":"Wang","year":"2022","journal-title":"J. Med. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Jin, Y.H., Jeon, S., Lee, J., Kim, S., Jang, M.S., Park, C.M., Song, J.H., Kim, H.R., and Kwon, S. (2021). Broad spectrum antiviral properties of cardiotonic steroids used as potential therapeutics for emerging coronavirus infections. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13111839"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2603","DOI":"10.1056\/NEJMoa2034577","article-title":"Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine","volume":"383","author":"Polack","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/s41541-021-00356-x","article-title":"Adenoviral vector vaccine platforms in the SARS-CoV-2 pandemic","volume":"6","author":"Mendonca","year":"2021","journal-title":"NPJ Vaccines"},{"key":"ref_22","first-page":"2101","article-title":"Novavax COVID-19 vaccine booster authorized","volume":"328","author":"Larkin","year":"2022","journal-title":"JAMA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"100654","DOI":"10.1016\/j.lanwpc.2022.100654","article-title":"Comparative effectiveness of 3 or 4 doses of mRNA and inactivated whole-virus vaccines against COVID-19 infection, hospitalization and severe outcomes among elderly in Singapore","volume":"29","author":"Tan","year":"2022","journal-title":"Lancet Reg. Health West. Pac."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/s41577-021-00592-1","article-title":"Progress of the COVID-19 vaccine effort: Viruses, vaccines and variants versus efficacy, effectiveness and escape","volume":"21","author":"Tregoning","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1038\/s41577-021-00542-x","article-title":"Neutralizing monoclonal antibodies for treatment of COVID-19","volume":"21","author":"Taylor","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.bj.2020.11.011","article-title":"Neutralizing monoclonal antibodies for COVID-19 treatment and prevention","volume":"44","author":"Jaworski","year":"2021","journal-title":"Biomed. J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1016\/S1473-3099(22)00495-9","article-title":"A monoclonal antibody stands out against omicron subvariants: A call to action for a wider access to bebtelovimab","volume":"22","author":"Hentzien","year":"2022","journal-title":"Lancet Infect. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1056\/NEJMoa2007764","article-title":"Remdesivir for the treatment of COVID-19\u2014Final report","volume":"383","author":"Beigel","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_29","unstructured":"(2020). An EUA for baricitinib (Olumiant) for COVID-19. Med. Lett. Drugs Ther., 62, 202\u2013203."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1080\/07853890.2022.2034936","article-title":"Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19: A meta-analysis","volume":"54","author":"Wen","year":"2022","journal-title":"Ann. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"28549","DOI":"10.3390\/ijms161226122","article-title":"Plants as factories for human pharmaceuticals: Applications and challenges","volume":"16","author":"Yao","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"El-Demerdash, A., Hassan, A., Abd El-Aziz, T.M., Stockand, J.D., and Arafa, R.K. (2021). Marine brominated tyrosine alkaloids as promising inhibitors of SARS-CoV-2. Molecules, 26.","DOI":"10.3390\/molecules26206171"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"113869","DOI":"10.1016\/j.jep.2021.113869","article-title":"Chinese herbal medicine: Fighting SARS-CoV-2 infection on all fronts","volume":"270","author":"Wang","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Sahoo, A., Fuloria, S., Swain, S.S., Panda, S.K., Sekar, M., Subramaniyan, V., Panda, M., Jena, A.K., Sathasivam, K.V., and Fuloria, N.K. (2021). Potential of marine terpenoids against SARS-CoV-2: An in silico drug development approach. Biomedicines, 9.","DOI":"10.3390\/biomedicines9111505"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Haddad, M., Gaudreault, R., Sasseville, G., Nguyen, P.T., Wiebe, H., Van De Ven, T., Bourgault, S., Mousseau, N., and Ramassamy, C. (2022). Molecular interactions of tannic acid with proteins associated with SARS-CoV-2 infectivity. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052643"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5384","DOI":"10.1002\/ptr.7151","article-title":"Natural products and phytochemicals as potential anti-SARS-CoV-2 drugs","volume":"35","author":"Merarchi","year":"2021","journal-title":"Phytother. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"444","DOI":"10.3389\/fmed.2020.00444","article-title":"Plants metabolites: Possibility of natural therapeutics against the COVID-19 pandemic","volume":"7","author":"Bhuiyan","year":"2020","journal-title":"Front. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"153359","DOI":"10.1016\/j.jplph.2020.153359","article-title":"Plant molecular farming for the production of valuable proteins\u2014Critical evaluation of achievements and future challenges","volume":"258\u2013259","author":"Schillberg","year":"2021","journal-title":"J. Plant Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"107519","DOI":"10.1016\/j.biotechadv.2020.107519","article-title":"Molecular farming\u2014The slope of enlightenment","volume":"40","author":"Fischer","year":"2020","journal-title":"Biotechnol Adv."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1056\/NEJMoa2201300","article-title":"Efficacy and safety of a recombinant plant-based adjuvanted COVID-19 vaccine","volume":"386","author":"Hager","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"594019","DOI":"10.3389\/fpls.2020.594019","article-title":"The Emergency Response Capacity of Plant-based biopharmaceutical manufacturing-what it is and what it could be","volume":"11","author":"Tuse","year":"2020","journal-title":"Front. Plant Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.tplants.2020.04.009","article-title":"Potential applications of plant biotechnology against SARS-CoV-2","volume":"25","author":"Capell","year":"2020","journal-title":"Trends Plant Sci."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Mahmood, N., Nasir, S.B., and Hefferon, K. (2020). Plant-based drugs and vaccines for COVID-19. Vaccines, 9.","DOI":"10.3390\/vaccines9010015"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ortega-Berlanga, B., and Pniewski, T. (2022). Plant-based vaccines in combat against coronavirus diseases. Vaccines, 10.","DOI":"10.3390\/vaccines10020138"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Pavlov, A., and Bley, T. (2016). Bioprocessing of Plant In Vitro Systems, Springer International Publishing AG. [1st ed.].","DOI":"10.1007\/978-3-319-32004-5"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Jugler, C., Sun, H., Nguyen, K., Palt, R., Felder, M., Steinkellner, H., and Chen, Q. (Plant Biotechnol. J., 2022). A novel plant-made monoclonal antibody enhances the synergetic potency of an antibody cocktail against the SARS-CoV-2 Omicron variant, Plant Biotechnol. J., published online ahead of print.","DOI":"10.1111\/pbi.13970"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Ruocco, V., and Strasser, R. (2022). Transient expression of glycosylated SARS-CoV-2 antigens in Nicotiana benthamiana. Plants, 11.","DOI":"10.3390\/plants11081093"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"720","DOI":"10.3389\/fpls.2019.00720","article-title":"Critical Analysis of the Commercial potential of plants for the production of recombinant proteins","volume":"10","author":"Schillberg","year":"2019","journal-title":"Front. Plant Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1111\/pbi.12428","article-title":"Large-scale production of pharmaceutical proteins in plant cell culture-the protalix experience","volume":"13","author":"Tekoah","year":"2015","journal-title":"Plant Biotechnol. J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1016\/S0140-6736(20)32014-6","article-title":"Efficacy, immunogenicity, and safety of a plant-derived, quadrivalent, virus-like particle influenza vaccine in adults (18\u201364 years) and older adults (>\/=65 years): Two multicentre, randomised phase 3 trials","volume":"396","author":"Ward","year":"2020","journal-title":"Lancet"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"682953","DOI":"10.3389\/fpls.2021.682953","article-title":"Plant-produced receptor-binding domain of SARS-CoV-2 elicits potent neutralizing responses in mice and non-human primates","volume":"12","author":"Siriwattananon","year":"2021","journal-title":"Front. Plant Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1126\/science.abc2241","article-title":"A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2","volume":"368","author":"Wu","year":"2020","journal-title":"Science"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"742875","DOI":"10.3389\/fpls.2021.742875","article-title":"Soluble human angiotensin- converting enzyme 2 as a potential therapeutic tool for COVID-19 is produced at high levels in Nicotiana benthamiana plant with potent anti-SARS-CoV-2 activity","volume":"12","author":"Mamedov","year":"2021","journal-title":"Front. Plant Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2057832","DOI":"10.1080\/19420862.2022.2057832","article-title":"David versus goliath: ACE2-Fc receptor traps as potential SARS-CoV-2 inhibitors","volume":"14","author":"Alfaleh","year":"2022","journal-title":"MAbs"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1007\/s12250-020-00305-3","article-title":"Griffithsin with a broad-spectrum antiviral activity by binding glycans in viral glycoprotein exhibits strong synergistic effect in combination with a pan-coronavirus fusion inhibitor targeting SARS-CoV-2 spike S2 subunit","volume":"35","author":"Cai","year":"2020","journal-title":"Virol. Sin."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"927306","DOI":"10.3389\/fmicb.2022.927306","article-title":"A comprehensive review of the protein subunit vaccines against COVID-19","volume":"13","author":"Heidary","year":"2022","journal-title":"Front. Microbiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"790121","DOI":"10.3389\/fmicb.2021.790121","article-title":"Virus-like particles: Revolutionary platforms for developing vaccines against emerging infectious diseases","volume":"12","author":"Tariq","year":"2021","journal-title":"Front. Microbiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1002\/cmdc.201200487","article-title":"Modern subunit vaccines: Development, components, and research opportunities","volume":"8","author":"Moyle","year":"2013","journal-title":"ChemMedChem"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Peyret, H., Steele, J.F.C., Jung, J.W., Thuenemann, E.C., Meshcheriakova, Y., and Lomonossoff, G.P. (2021). Producing vaccines against enveloped viruses in plants: Making the impossible, difficult. Vaccines, 9.","DOI":"10.3390\/vaccines9070780"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"909958","DOI":"10.3389\/fddev.2022.909958","article-title":"Plant-based vaccines against COVID-19 for massive vaccination in Africa","volume":"2","author":"Hamdi","year":"2022","journal-title":"Front. Drug Deliv."},{"key":"ref_61","unstructured":"(2022, December 01). Medicago Covifenz COVID-19 Vaccine. Available online: https:\/\/www.canada.ca\/en\/health-canada\/services\/drugs-health-products\/covid19-industry\/drugs-vaccines-treatments\/vaccines\/medicago.html#a4."},{"key":"ref_62","unstructured":"(2022, December 02). COVID-19 Vaccine Development and Approvals Tracker. Available online: https:\/\/covid19.trackvaccines.org."},{"key":"ref_63","unstructured":"(2022, December 01). KBP-201 COVID-19 Vaccine Trial in Healthy Volunteers, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04473690."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Demarco, J.K., Royal, J.M., Severson, W.E., Gabbard, J.D., Hume, S., Morton, J., Swope, K., Simpson, C.A., Shepherd, J.W., and Bratcher, B. (2021). CoV-RBD121-NP vaccine candidate protects against symptomatic disease following SARS-CoV-2 challenge in K18-hACE2 mice and induces protective responses that prevent COVID-19-associated immunopathology. Vaccines, 9.","DOI":"10.3390\/vaccines9111346"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Royal, J.M., Simpson, C.A., McCormick, A.A., Phillips, A., Hume, S., Morton, J., Shepherd, J., Oh, Y., Swope, K., and De Beauchamp, J.L. (2021). Development of a SARS-CoV-2 vaccine candidate using plant-based manufacturing and a tobacco mosaic virus-like nano-particle. Vaccines, 9.","DOI":"10.3390\/vaccines9111347"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Maharjan, P.M., and Choe, S. (2021). Plant-based COVID-19 vaccines: Current status, design, and development strategies of candidate vaccines. Vaccines, 9.","DOI":"10.3390\/vaccines9090992"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"13","DOI":"10.7774\/cevr.2021.10.1.13","article-title":"Current updates and research on plant-based vaccines for coronavirus disease 2019","volume":"10","author":"Kadiresen","year":"2021","journal-title":"Clin. Exp. Vaccine Res."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Balieu, J., Jung, J.W., Chan, P., Lomonossoff, G.P., Lerouge, P., and Bardor, M. (2022). Investigation of the N-glycosylation of the SARS-CoV-2 S protein contained in VLPs produced in Nicotiana benthamiana. Molecules, 27.","DOI":"10.3390\/molecules27165119"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4440","DOI":"10.1016\/j.vaccine.2022.05.087","article-title":"Preclinical evaluation of a plant-derived SARS-CoV-2 subunit vaccine: Protective efficacy, immunogenicity, safety, and toxicity","volume":"40","author":"Shanmugaraj","year":"2022","journal-title":"Vaccine"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Mamedov, T., Yuksel, D., Ilgin, M., Gurbuzaslan, I., Gulec, B., Yetiskin, H., Uygut, M.A., Islam Pavel, S.T., Ozdarendeli, A., and Mammadova, G. (2021). Plant-produced glycosylated and in vivo deglycosylated receptor binding domain proteins of SARS-CoV-2 Induce potent neutralizing responses in mice. Viruses, 13.","DOI":"10.3390\/v13081595"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"17698","DOI":"10.1038\/s41598-020-74904-1","article-title":"Rapid production of SARS-CoV-2 receptor binding domain (RBD) and spike specific monoclonal antibody CR3022 in Nicotiana benthamiana","volume":"10","author":"Rattanapisit","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Demone, J., Maltseva, M., Nourimand, M., Nasr-Sharif, M., Galipeau, Y., Alarcon, E.I., Langlois, M.A., and MacLean, A.M. (2022). Scalable agroinfiltration-based production of SARS-CoV-2 antigens for use in diagnostic assays and subunit vaccines. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0277668"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"995429","DOI":"10.3389\/fpls.2022.995429","article-title":"Production of the SARS-CoV-2 spike protein and its receptor binding domain in plant cell suspension cultures","volume":"13","author":"Rebelo","year":"2022","journal-title":"Front. Plant Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"JC52","DOI":"10.7326\/J22-0028","article-title":"In adults who had not had COVID-19, Novavax vaccine had 90% efficacy at >\/=7 d after the second dose","volume":"175","author":"Granwehr","year":"2022","journal-title":"Ann. Intern. Med."},{"key":"ref_75","first-page":"873","article-title":"Efficacy and effectiveness of COVID-19 vaccine\u2014Absolute vs. relative risk reduction. Expert Rev","volume":"21","author":"Marabotti","year":"2022","journal-title":"Vaccines"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Mardanova, E.S., Kotlyarov, R.Y., and Ravin, N.V. (2021). High-yield production of receptor binding domain of SARS-CoV-2 linked to bacterial flagellin in plants using self-replicating viral vector pEff. Plants, 10.","DOI":"10.3390\/plants10122682"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"901978","DOI":"10.3389\/fpls.2022.901978","article-title":"A recombinant subunit vaccine candidate produced in plants elicits neutralizing antibodies against SARS-CoV-2 variants in macaques","volume":"13","author":"Khorattanakulchai","year":"2022","journal-title":"Front. Plant Sci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"4265","DOI":"10.1002\/jmv.27881","article-title":"Receptor binding domain proteins of SARS-CoV-2 variants produced in Nicotiana benthamiana elicit neutralizing antibodies against variants of concern","volume":"94","author":"Khorattanakulchai","year":"2022","journal-title":"J. Med. Virol."},{"key":"ref_79","unstructured":"Phoolcharoen, W. Personal communication."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s12951-021-00806-7","article-title":"Virus-like particles: Preparation, immunogenicity and their roles as nanovaccines and drug nanocarriers","volume":"19","author":"Nooraei","year":"2021","journal-title":"J. Nanobiotechnol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.vaccine.2012.10.083","article-title":"Virus-like particles as a highly efficient vaccine platform: Diversity of targets and production systems and advances in clinical development","volume":"31","author":"Kushnir","year":"2012","journal-title":"Vaccine"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.aivir.2016.09.002","article-title":"Biomedical and Catalytic Opportunities of Virus-Like Particles in Nanotechnology","volume":"97","author":"Schwarz","year":"2017","journal-title":"Adv. Virus Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1038\/s41591-021-01370-1","article-title":"Phase 1 randomized trial of a plant-derived virus-like particle vaccine for COVID-19","volume":"27","author":"Ward","year":"2021","journal-title":"Nat. Med."},{"key":"ref_84","unstructured":"(2022, December 01). iBio Reports Preliminary Unaudited Fiscal Year 2022 Financial Results and Provides Corporate Update. Available online: https:\/\/www.globenewswire.com\/news-release\/2022\/09\/27\/2523812\/0\/en\/iBio-Reports-Preliminary-Unaudited-Fiscal-Year-2022-Financial-Results-and-Provides-Corporate-Update.html#:~:text=Preliminary%20Unaudited%20Financial%20Results%3A,comparable%20period%20in%20fiscal%202021."},{"key":"ref_85","unstructured":"(2022, December 02). Pipeline Therapeutic Candidates. Available online: https:\/\/ibioinc.com\/pipeline\/."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12929-019-0592-z","article-title":"Development of therapeutic antibodies for the treatment of diseases","volume":"27","author":"Lu","year":"2020","journal-title":"J. Biomed. Sci."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Jugler, C., Sun, H., Grill, F., Kibler, K., Esqueda, A., Lai, H., Li, Y., Lake, D., and Chen, Q. (2022). Potential for a plant-made SARS-CoV-2 neutralizing monoclonal antibody as a synergetic cocktail component. Vaccines, 10.","DOI":"10.3390\/vaccines10050772"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.coviro.2021.12.005","article-title":"Development of plant-made monoclonal antibodies against viral infections","volume":"52","author":"Chen","year":"2022","journal-title":"Curr. Opin. Virol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1111\/pbi.12416","article-title":"Regulatory approval and a first-in-human phase I clinical trial of a monoclonal antibody produced in transgenic tobacco plants","volume":"13","author":"Ma","year":"2015","journal-title":"Plant Biotechnol. J."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"589995","DOI":"10.3389\/fpls.2020.589995","article-title":"Monoclonal antibodies B38 and H4 produced in Nicotiana benthamiana neutralize SARS-CoV-2 in vitro","volume":"11","author":"Shanmugaraj","year":"2020","journal-title":"Front. Plant Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e2107249118","DOI":"10.1073\/pnas.2107249118","article-title":"Highly active engineered IgG3 antibodies against SARS-CoV-2","volume":"118","author":"Kallolimath","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1111\/pbi.13813","article-title":"Plant-based expression and characterization of SARS-CoV-2 virus-like particles presenting a native spike protein","volume":"20","author":"Jung","year":"2022","journal-title":"Plant Biotechnol. J."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1038\/s41591-021-01678-y","article-title":"An infectious SARS-CoV-2 B.1.1.529 Omicron virus escapes neutralization by therapeutic monoclonal antibodies","volume":"28","author":"VanBlargan","year":"2022","journal-title":"Nat. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"105193","DOI":"10.1016\/j.isci.2022.105193","article-title":"Anti-SARS-CoV-2 immunoadhesin remains effective against Omicron and other emerging variants of concern","volume":"25","author":"Weinstein","year":"2022","journal-title":"iScience"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/0167-7799(96)80921-8","article-title":"Immunoadhesins: Principles and applications","volume":"14","author":"Chamow","year":"1996","journal-title":"Trends Biotechnol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"eabn4188","DOI":"10.1126\/sciadv.abn4188","article-title":"Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities","volume":"8","author":"Chen","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.virol.2014.02.005","article-title":"Phagocytic cells contribute to the antibody-mediated elimination of pulmonary-infected SARS coronavirus","volume":"454\u2013455","author":"Yasui","year":"2014","journal-title":"Virology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"604663","DOI":"10.3389\/fpls.2020.604663","article-title":"Development of plant-produced recombinant ACE2-Fc fusion protein as a potential therapeutic agent against SARS-CoV-2","volume":"11","author":"Siriwattananon","year":"2021","journal-title":"Front. Plant Sci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"28046","DOI":"10.1073\/pnas.2016093117","article-title":"Engineered ACE2 receptor traps potently neutralize SARS-CoV-2","volume":"117","author":"Glasgow","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"3802","DOI":"10.1038\/s41467-021-24013-y","article-title":"Engineered ACE2 receptor therapy overcomes mutational escape of SARS-CoV-2","volume":"12","author":"Higuchi","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Bernardi, A., Huang, Y., Harris, B., Xiong, Y., Nandi, S., McDonald, K.A., and Faller, R. (2020). Development and simulation of fully glycosylated molecular models of ACE2-Fc fusion proteins and their interaction with the SARS-CoV-2 spike protein binding domain. PLoS ONE, 15.","DOI":"10.1101\/2020.05.05.079558"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Mou, H., Quinlan, B.D., Peng, H., Liu, G., Guo, Y., Peng, S., Zhang, L., Davis-Gardner, M.E., Gardner, M.R., and Crynen, G. (2021). Mutations derived from horseshoe bat ACE2 orthologs enhance ACE2-Fc neutralization of SARS-CoV-2. PLoS Pathog., 17.","DOI":"10.1101\/2020.06.29.178459"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1126\/science.abc0870","article-title":"Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2","volume":"369","author":"Chan","year":"2020","journal-title":"Science"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"108528","DOI":"10.1016\/j.celrep.2020.108528","article-title":"An ACE2 microbody containing a single immunoglobulin Fc domain is a potent inhibitor of SARS-CoV-2","volume":"33","author":"Tada","year":"2020","journal-title":"Cell Rep."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"105271","DOI":"10.1016\/j.antiviral.2022.105271","article-title":"ACE2-Fc fusion protein overcomes viral escape by potently neutralizing SARS-CoV-2 variants of concern","volume":"199","author":"Tsai","year":"2022","journal-title":"Antivir. Res."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"e2000566","DOI":"10.1002\/biot.202000566","article-title":"Generation of enzymatically competent SARS-CoV-2 decoy receptor ACE2-Fc in glycoengineered Nicotiana benthamiana","volume":"16","author":"Castilho","year":"2021","journal-title":"Biotechnol. J."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1016\/j.ymthe.2021.11.008","article-title":"Debulking SARS-CoV-2 in saliva using angiotensin converting enzyme 2 in chewing gum to decrease oral virus transmission and infection","volume":"30","author":"Daniell","year":"2022","journal-title":"Mol. Ther."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"121671","DOI":"10.1016\/j.biomaterials.2022.121671","article-title":"Debulking different Corona (SARS-CoV-2 delta, omicron, OC43) and influenza (H1N1, H3N2) virus strains by plant viral trap proteins in chewing gums to decrease infection and transmission","volume":"288","author":"Daniell","year":"2022","journal-title":"Biomaterials"},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Ganesan, P.K., Kulchar, R.J., Kaznica, P., Montoya-Lopez, R., Green, B.J., Streatfield, S.J., and Daniell, H. (Plant Biotechnol. J., 2022). Optimization of biomass and target protein yield for Phase III clinical trial to evaluate Angiotensin Converting Enzyme 2 expressed in lettuce chloroplasts to reduce SARS-CoV-2 infection and transmission, Plant Biotechnol. J., published online ahead of print.","DOI":"10.1111\/pbi.13954"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"280","DOI":"10.34297\/AJBSR.2021.12.001757","article-title":"Lectins; a hope of treatment for COVID-19","volume":"12","author":"Ghafoor","year":"2021","journal-title":"Am. J. Biomed. Sci. Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"112507","DOI":"10.1016\/j.biopha.2021.112507","article-title":"Plant lectins as prospective antiviral biomolecules in the search for COVID-19 eradication strategies","volume":"146","author":"Ahmed","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"12239","DOI":"10.1007\/s11033-022-07854-8","article-title":"Lectins from plants and algae act as anti-viral against HIV, influenza and coronaviruses","volume":"49","author":"Naik","year":"2022","journal-title":"Mol. Biol. Rep."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Barre, A., Van Damme, E.J.M., Simplicien, M., Le Poder, S., Klonjkowski, B., Benoist, H., Peyrade, D., and Rouge, P. (2021). Man-Specific lectins from plants, fungi, algae and cyanobacteria, as potential blockers for SARS-CoV, MERS-CoV and SARS-CoV-2 (COVID-19) Coronaviruses: Biomedical perspectives. Cells, 10.","DOI":"10.3390\/cells10071619"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1093\/glycob\/cwaa099","article-title":"Exploring lectin-glycan interactions to combat COVID-19: Lessons acquired from other enveloped viruses","volume":"31","author":"Mendonca","year":"2021","journal-title":"Glycobiology"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"100774","DOI":"10.1016\/j.xcrm.2022.100774","article-title":"A molecularly engineered, broad-spectrum anti-coronavirus lectin inhibits SARS-CoV-2 and MERS-CoV infection in vivo","volume":"3","author":"Chan","year":"2022","journal-title":"Cell Rep. Med."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"108016","DOI":"10.1016\/j.celrep.2020.108016","article-title":"A carbohydrate-binding protein from the edible lablab beans effectively blocks the infections of influenza viruses and SARS-CoV-2","volume":"32","author":"Liu","year":"2020","journal-title":"Cell Rep."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Lee, C. (2019). Griffithsin, a highly potent broad-spectrum antiviral lectin from red algae: From discovery to clinical application. Mar. Drugs, 17.","DOI":"10.3390\/md17100567"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1021\/acsinfecdis.2c00006","article-title":"A highly potent SARS-CoV-2 blocking lectin protein","volume":"8","author":"Ahan","year":"2022","journal-title":"ACS Infect. Dis."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"3880","DOI":"10.1080\/07391102.2020.1851303","article-title":"Sensing the interactions between carbohydrate-binding agents and N-linked glycans of SARS-CoV-2 spike glycoprotein using molecular docking and simulation studies","volume":"40","author":"Lokhande","year":"2022","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s11658-022-00338-4","article-title":"Lectins and lectibodies: Potential promising antiviral agents","volume":"27","author":"Heydari","year":"2022","journal-title":"Cell Mol. Biol. Lett."},{"key":"ref_121","first-page":"52459","article-title":"A comparative analysis of recombinant protein expression in different biofactories: Bacteria, insect cells and plant systems","volume":"97","author":"Gecchele","year":"2015","journal-title":"J. Vis. Exp."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1111\/j.1467-7652.2009.00497.x","article-title":"Plant-specific glycosylation patterns in the context of therapeutic protein production","volume":"8","author":"Gomord","year":"2010","journal-title":"Plant Biotechnol. J."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1186\/s40001-022-00818-5","article-title":"Traditional herbs against COVID-19: Back to old weapons to combat the new pandemic","volume":"27","author":"Elekhnawy","year":"2022","journal-title":"Eur. J. Med. Res."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1002\/ptr.6700","article-title":"Natural products and their derivatives against coronavirus: A review of the non-clinical and pre-clinical data","volume":"34","author":"Islam","year":"2020","journal-title":"Phytother. Res."},{"key":"ref_125","first-page":"e26549","article-title":"Effects of plant metabolites on the growth of COVID-19 (Coronavirus Disease-19) including omicron strain","volume":"14","author":"Bagde","year":"2022","journal-title":"Cureus"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"114070","DOI":"10.1016\/j.jviromet.2021.114070","article-title":"Antiviral activity of bioactive phytocompounds against coronavirus: An update","volume":"290","author":"Bhattacharya","year":"2021","journal-title":"J. Virol. Methods"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"669362","DOI":"10.3389\/fphar.2021.669362","article-title":"Oral curcumin with piperine as adjuvant therapy for the treatment of COVID-19: A randomized clinical trial","volume":"12","author":"Pawar","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Bhar, A., Jain, A., and Das, S. (Vegetos, 2022). Natural therapeutics against SARS-CoV-2: The potentiality and challenges, Vegetos, published online ahead of print.","DOI":"10.1007\/s42535-022-00401-7"},{"key":"ref_129","first-page":"84","article-title":"Plant-derived metabolites as potent inhibitor and treatment for COVID-19","volume":"10","author":"Holghoomi","year":"2022","journal-title":"J. Pharm. Care"},{"key":"ref_130","doi-asserted-by":"crossref","unstructured":"Lopes, A.J.O., Calado, G.P., Froes, Y.N., Araujo, S.A., Franca, L.M., Paes, A.M.A., Morais, S.V., Rocha, C.Q.D., and Vasconcelos, C.C. (2022). Plant metabolites as SARS-CoV-2 inhibitors candidates: In silico and in vitro studies. Pharmaceuticals, 15.","DOI":"10.3390\/ph15091045"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"153930","DOI":"10.1016\/j.phymed.2022.153930","article-title":"Role of medicinal plants in inhibiting SARS-CoV-2 and in the management of post-COVID-19 complications","volume":"98","author":"Mukherjee","year":"2022","journal-title":"Phytomedicine"},{"key":"ref_132","doi-asserted-by":"crossref","unstructured":"Llivisaca-Contreras, S.A., Naranjo-Moran, J., Pino-Acosta, A., Pieters, L., Vanden Berghe, W., Manzano, P., Vargas-Perez, J., Leon-Tamariz, F., and Cevallos-Cevallos, J.M. (2021). Plants and natural products with activity against various types of coronaviruses: A review with focus on SARS-CoV-2. Molecules, 26.","DOI":"10.3390\/molecules26134099"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"42404","DOI":"10.1007\/s11356-022-19770-2","article-title":"Targeting natural products against SARS-CoV-2","volume":"29","author":"Behl","year":"2022","journal-title":"Environ. Sci Pollut. Res. Int."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"2415","DOI":"10.2174\/1381612828666220722124826","article-title":"An update on promising agents against COVID-19: Secondary metabolites and mechanistic aspects","volume":"28","author":"Jamshidnia","year":"2022","journal-title":"Curr. Pharm. Des."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1007\/s11094-021-02540-8","article-title":"The effect of phytocompounds of medicinal plants on coronavirus (2019-NCOV) infection","volume":"55","author":"Zrig","year":"2022","journal-title":"Pharm. Chem. J."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"289","DOI":"10.3390\/jox12040020","article-title":"Antiviral and anti-inflammatory plant-derived bioactive compounds and their potential use in the treatment of COVID-19-related pathologies","volume":"12","author":"Trivedi","year":"2022","journal-title":"J. Xenobiot."},{"key":"ref_137","doi-asserted-by":"crossref","unstructured":"Yang, L., and Wang, Z. (2021). Natural products, alone or in combination with FDA-Approved drugs, to treat COVID-19 and lung cancer. Biomedicines, 9.","DOI":"10.3390\/biomedicines9060689"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"101890","DOI":"10.1016\/j.bcab.2020.101890","article-title":"Therapeutic potential of medicinal plants against COVID-19: The role of antiviral medicinal metabolites","volume":"31","author":"Khan","year":"2021","journal-title":"Biocatal. Agric. Biotechnol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"589044","DOI":"10.3389\/fphar.2020.589044","article-title":"A Review on Plant Bioactive Compounds and Their Modes of Action Against Coronavirus Infection","volume":"11","author":"Remali","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s12275-022-1499-z","article-title":"Coronavirus enzyme inhibitors-experimentally proven natural compounds from plants","volume":"60","author":"Park","year":"2022","journal-title":"J. Microbiol."},{"key":"ref_141","first-page":"166","article-title":"In silico identification of potent FDA approved drugs against Coronavirus COVID-19 main protease: A drug repurposing approach","volume":"7","author":"Kumar","year":"2020","journal-title":"Chem. Biol. Lett."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"6249","DOI":"10.1080\/07391102.2020.1796810","article-title":"Plant-derived natural polyphenols as potential antiviral drugs against SARS-CoV-2 via RNA-dependent RNA polymerase (RdRp) inhibition: An in-silico analysis","volume":"39","author":"Singh","year":"2021","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"e2021579118","DOI":"10.1073\/pnas.2021579118","article-title":"Identification of existing pharmaceuticals and herbal medicines as inhibitors of SARS-CoV-2 infection","volume":"118","author":"Jan","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Muchtaridi, M., Fauzi, M., Khairul Ikram, N.K., Mohd Gazzali, A., and Wahab, H.A. (2020). Natural flavonoids as potential angiotensin-converting enzyme 2 inhibitors for anti-SARS-CoV-2. Molecules, 25.","DOI":"10.3390\/molecules25173980"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"13982","DOI":"10.1021\/acs.jafc.0c05064","article-title":"Quercetin and Its Metabolites Inhibit Recombinant Human Angiotensin-Converting Enzyme 2 (ACE2) Activity","volume":"68","author":"Liu","year":"2020","journal-title":"J. Agric. Food Chem."},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Senthil Kumar, K.J., Gokila Vani, M., Wang, C.S., Chen, C.C., Chen, Y.C., Lu, L.P., Huang, C.H., Lai, C.S., and Wang, S.Y. (2020). Geranium and lemon essential oils and their active compounds downregulate angiotensin-converting enzyme 2 (ACE2), a SARS-CoV-2 spike receptor-binding domain, in epithelial cells. Plants, 9.","DOI":"10.3390\/plants9060770"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"589783","DOI":"10.3389\/fpls.2021.589783","article-title":"Cinnamon and hop extracts as potential immunomodulators for severe COVID-19 cases","volume":"12","author":"Lucas","year":"2021","journal-title":"Front. Plant Sci."},{"key":"ref_148","first-page":"3396","article-title":"Potential inhibitors of coronavirus 3-chymotrypsin-like protease (3CL(pro)): An in silico screening of alkaloids and terpenoids from African medicinal plants","volume":"39","author":"Gyebi","year":"2021","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_149","doi-asserted-by":"crossref","unstructured":"Wink, M. (2020). Potential of DNA intercalating alkaloids and other plant secondary metabolites against SARS-CoV-2 causing COVID-19. Diversity, 12.","DOI":"10.3390\/d12050175"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"2686","DOI":"10.1002\/ptr.7442","article-title":"The naturally-derived alkaloids as a potential treatment for COVID-19: A scoping review","volume":"36","author":"Gonzalez","year":"2022","journal-title":"Phytother. Res."},{"key":"ref_151","doi-asserted-by":"crossref","unstructured":"Truzzi, F., Tibaldi, C., Zhang, Y., Dinelli, G., and D\u2019Ammen, E. (2021). An overview on dietary polyphenols and their biopharmaceutical classification system (BCS). Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115514"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"e10702","DOI":"10.1016\/j.heliyon.2022.e10702","article-title":"Phenolic compounds versus SARS-CoV-2: An update on the main findings against COVID-19","volume":"8","year":"2022","journal-title":"Heliyon"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"240","DOI":"10.3389\/fmed.2020.00240","article-title":"May polyphenols have a role against coronavirus infection? An overview of in vitro evidence","volume":"7","author":"Annunziata","year":"2020","journal-title":"Front. Med."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"2683286","DOI":"10.1155\/2020\/2683286","article-title":"Design of a multiepitope-based peptide vaccine against the e protein of human COVID-19: An immunoinformatics approach","volume":"2020","author":"Abdelmageed","year":"2020","journal-title":"Biomed. Res. Int."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"19570","DOI":"10.1039\/D0RA03582C","article-title":"Molecular docking reveals the potential of Salvadora persica flavonoids to inhibit COVID-19 virus main protease","volume":"10","author":"Owis","year":"2020","journal-title":"RSC Adv."},{"key":"ref_156","doi-asserted-by":"crossref","unstructured":"Sytar, O., Brestic, M., Hajihashemi, S., Skalicky, M., Kubes, J., Lamilla-Tamayo, L., Ibrahimova, U., Ibadullayeva, S., and Landi, M. (2021). COVID-19 prophylaxis efforts based on natural antiviral plant extracts and their compounds. Molecules, 26.","DOI":"10.3390\/molecules26030727"},{"key":"ref_157","first-page":"214","article-title":"Plant-microbe interactions and secondary metabolites with antibacterial, antifungal and antiviral properties","volume":"Volume 39","author":"Wink","year":"2010","journal-title":"Annual Plant Reviews: Functions and Biotechnology of Plant Secondary Metabolites"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1007\/s10787-022-00939-7","article-title":"Advancing combination treatment with glycyrrhizin and boswellic acids for hospitalized patients with moderate COVID-19 infection: A randomized clinical trial","volume":"30","author":"Gomaa","year":"2022","journal-title":"Inflammopharmacology"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"114016","DOI":"10.1016\/j.jep.2021.114016","article-title":"Artemisia annua L. extracts inhibit the in vitro replication of SARS-CoV-2 and two of its variants","volume":"274","author":"Nair","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"114797","DOI":"10.1016\/j.jep.2021.114797","article-title":"Artemisia annua L. hot-water extracts show potent activity in vitro against COVID-19 variants including delta","volume":"284","author":"Nair","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"14571","DOI":"10.1038\/s41598-021-93361-y","article-title":"In vitro efficacy of artemisinin-based treatments against SARS-CoV-2","volume":"11","author":"Zhou","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"105428","DOI":"10.1016\/j.antiviral.2022.105428","article-title":"Astersaponin I from Aster koraiensis is a natural viral fusion blocker that inhibits the infection of SARS-CoV-2 variants and syncytium formation","volume":"208","author":"Kim","year":"2022","journal-title":"Antivir. Res."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"105552","DOI":"10.1016\/j.compbiomed.2022.105552","article-title":"Curcumin inhibits spike protein of new SARS-CoV-2 variant of concern (VOC) Omicron, an in silico study","volume":"146","author":"Nag","year":"2022","journal-title":"Comput. Biol. Med."},{"key":"ref_164","first-page":"387","article-title":"Different aspects of emetine\u2019s capabilities as a highly potent SARS-CoV-2 inhibitor against COVID-19. ACS Pharmacol","volume":"5","author":"Valipour","year":"2022","journal-title":"Transl. Sci."},{"key":"ref_165","doi-asserted-by":"crossref","unstructured":"Cheng, F.J., Huynh, T.K., Yang, C.S., Hu, D.W., Shen, Y.C., Tu, C.Y., Wu, Y.C., Tang, C.H., Huang, W.C., and Chen, Y. (2021). Hesperidin is a potential inhibitor against SARS-CoV-2 infection. Nutrients, 13.","DOI":"10.3390\/nu13082800"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"14025","DOI":"10.1021\/acsami.1c22439","article-title":"The interaction of hypericin with SARS-CoV-2 reveals a multimodal antiviral activity","volume":"14","author":"Delcanale","year":"2022","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.jare.2021.11.012","article-title":"Natural triterpenoids from licorice potently inhibit SARS-CoV-2 infection","volume":"36","author":"Yi","year":"2022","journal-title":"J. Adv. Res."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"10571","DOI":"10.1038\/s41598-022-14664-2","article-title":"Quercetin and luteolin are single-digit micromolar inhibitors of the SARS-CoV-2 RNA-dependent RNA polymerase","volume":"12","author":"Munafo","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"669642","DOI":"10.3389\/fphar.2021.669642","article-title":"Myricetin inhibits SARS-CoV-2 viral replication by targeting M(pro) and ameliorates pulmonary inflammation","volume":"12","author":"Xiao","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"11120","DOI":"10.1038\/s41598-022-15288-2","article-title":"In silico screening of some compounds derived from the desert medicinal plant Rhazya stricta for the potential treatment of COVID-19","volume":"12","author":"Baeshen","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"19963","DOI":"10.1038\/s41598-020-77003-3","article-title":"High-content screening of Thai medicinal plants reveals Boesenbergia rotunda extract and its component Panduratin A as anti-SARS-CoV-2 agents","volume":"10","author":"Kanjanasirirat","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"23695","DOI":"10.1038\/s41598-021-03149-3","article-title":"Persimmon-derived tannin has antiviral effects and reduces the severity of infection and transmission of SARS-CoV-2 in a Syrian hamster model","volume":"11","author":"Furukawa","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_173","doi-asserted-by":"crossref","unstructured":"Shekunov, E.V., Efimova, S.S., Yudintceva, N.M., Muryleva, A.A., Zarubaev, V.V., Slita, A.V., and Ostroumova, O.S. (2021). Plant alkaloids inhibit membrane fusion mediated by calcium and fragments of MERS-CoV and SARS-CoV\/SARS-CoV-2 fusion peptides. Biomedicines, 9.","DOI":"10.3390\/biomedicines9101434"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/j.tips.2022.04.004","article-title":"Thapsigargin: Key to new host-directed coronavirus antivirals?","volume":"43","author":"Shaban","year":"2022","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"623795","DOI":"10.3389\/fphar.2021.623795","article-title":"Withania somnifera (L.) Dunal: Opportunity for Clinical Repurposing in COVID-19 Management","volume":"12","author":"Saggam","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"780257","DOI":"10.3389\/fpls.2022.780257","article-title":"Artemisinins in combating viral infections like SARS-CoV-2, inflammation and cancers and options to meet increased global demand","volume":"13","author":"Babaei","year":"2022","journal-title":"Front. Plant Sci."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.3389\/fphar.2020.01013","article-title":"Turning the tide: Natural products and natural-product-inspired chemicals as potential counters to SARS-CoV-2 infection","volume":"11","author":"Wang","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s43556-020-00018-9","article-title":"Low dose of emetine as potential anti-SARS-CoV-2 virus therapy: Preclinical in vitro inhibition and in vivo pharmacokinetic evidences","volume":"1","author":"Wang","year":"2020","journal-title":"Mol. Biomed."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/s41401-021-00668-7","article-title":"A multi-targeting drug design strategy for identifying potent anti-SARS-CoV-2 inhibitors","volume":"43","author":"Ren","year":"2022","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"105056","DOI":"10.1016\/j.antiviral.2021.105056","article-title":"Emetine suppresses SARS-CoV-2 replication by inhibiting interaction of viral mRNA with eIF4E","volume":"189","author":"Kumar","year":"2021","journal-title":"Antivir. Res."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"152691","DOI":"10.1016\/j.scitotenv.2021.152691","article-title":"Pharmaceutical compounds used in the COVID-19 pandemic: A review of their presence in water and treatment techniques for their elimination","volume":"814","year":"2022","journal-title":"Sci. Total Environ."},{"key":"ref_182","doi-asserted-by":"crossref","unstructured":"Weidenbacher, P.A., Sanyal, M., Friedland, N., Tang, S., Arunachalam, P.S., Hu, M., Kumru, O.S., Morris, M.K., Fontenot, J., and Shirreff, L. (2022). A ferritin-based COVID-19 nanoparticle vaccine that elicits robust, durable, broad-spectrum neutralizing antisera in non-human primates. bioRxiv, preprint.","DOI":"10.1101\/2022.12.25.521784"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41541-022-00485-x","article-title":"Towards the future exploration of mucosal mRNA vaccines against emerging viral diseases; lessons from existing next-generation mucosal vaccine strategies","volume":"7","author":"Hameed","year":"2022","journal-title":"NPJ Vaccines"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/d41586-022-02824-3","article-title":"How nasal-spray vaccines could change the pandemic","volume":"609","author":"Waltz","year":"2022","journal-title":"Nature"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/d41586-022-02851-0","article-title":"China and India approve nasal COVID vaccines\u2014Are they a game changer?","volume":"609","author":"Waltz","year":"2022","journal-title":"Nature"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1111\/pbi.12471","article-title":"Plant-made oral vaccines against human infectious diseases-Are we there yet?","volume":"13","author":"Chan","year":"2015","journal-title":"Plant Biotechnol. J."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1016\/j.biotechadv.2011.08.020","article-title":"Green factory: Plants as bioproduction platforms for recombinant proteins","volume":"30","author":"Xu","year":"2012","journal-title":"Biotechnol. Adv."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"499","DOI":"10.4155\/pbp.14.32","article-title":"On the way to commercializing plant cell culture platform for biopharmaceuticals: Present status and prospect","volume":"2","author":"Xu","year":"2014","journal-title":"Pharm. Bioprocess."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1007\/s00299-021-02693-6","article-title":"Cellular engineering of plant cells for improved therapeutic protein production","volume":"40","author":"Karki","year":"2021","journal-title":"Plant Cell Rep."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"e09739","DOI":"10.1016\/j.heliyon.2022.e09739","article-title":"The role of natural products from medicinal plants against COVID-19: Traditional medicine practice in Tanzania","volume":"8","author":"Mlozi","year":"2022","journal-title":"Heliyon"},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"eaaz0381","DOI":"10.1126\/sciadv.aaz0381","article-title":"Information theory tests critical predictions of plant defense theory for specialized metabolism","volume":"6","author":"Li","year":"2020","journal-title":"Sci. Adv."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/13\/3\/617\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:40:14Z","timestamp":1760121614000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/13\/3\/617"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,23]]},"references-count":191,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["life13030617"],"URL":"https:\/\/doi.org\/10.3390\/life13030617","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,23]]}}}