Plant bioactive compounds affecting biomarkers and final outcome of COVID-19

  • Darinka Gjorgieva Ackova University Goce Delčev - Faculty of Medical Sciences, Division of Pharmacy, Department of Applied Pharmacy
  • Viktorija Maksimova University Goce Delčev - Faculty of Medical Sciences, Division of Pharmacy, Department of Applied Pharmacy
  • Katarina Smilkov University Goce Delčev - Faculty of Medical Sciences, Division of Pharmacy, Department of Applied Pharmacy
Keywords: plant bioactive, treatment, COVID-19, biomarkers


Herbal medicinal products are known for their widespread use toward various viral infections and ease of disease symptoms. Therefore, the sudden appearance of the Severe Acute Respiratory Syndrome-related Coronavirus 2 (SARS-CoV-2) and COVID-19 disease was no exception. Bioactive compounds from natural plant origin could act on several disease levels: through essential immunological pathways, affecting COVID-19 biomarkers, or by halting or modulating SARS-CoV-2. In this paper, we review the recently published data regarding the use of plant bioactive compounds in the prevention/treatment of COVID-19. The mode of actions responsible for these effects is discussed, including the inhibition of attachment, penetration and release of the virus, actions affecting RNA, protein synthesis and viral proteases, as well as other mechanisms. The reviewed information suggests that plant bioactive compounds can be used alone or in combinations, but upcoming, extensive and global studies on several factors involved are needed to recognize indicative characteristics and various patterns of bioactive compounds use, related with an array of biomarkers connected to different elements of inflammatory and immune-related processes of COVID-19 disease.


Hu QF, Zhou B, Huang JM, Gao XM, Shu LD, Yang GY, et al. Antiviral phenolic compounds from Arundina gramnifolia. J Nat Prod. 2013;76(2):292–296.

Calland N, Dubuisson J, Rouillé Y, Séron K. Hepatitis C virus and natural compounds: a new antiviral approach? Viruses. 2012;4(10):2197–2217.

Sardi JCO, Scorzoni L, Bernardi T, Fusco-Almeida AM, Mendes Giannini MJS. Candida species: current epidemiology, pathogenicity, biofilm formation, natural antifungal products and new therapeutic options. J Med Microbiol. 2013;62:10–24.

Zhang B, Zhou X, Zhu C, Song Y, Feng F, Qiu Y, et al. Immune Phenotyping Based on the Neutrophil-to-Lymphocyte Ratio and IgG Level Predicts Disease Severity and Outcome for Patients With COVID-19. Front Mol Biosci. 2020;7:157.

Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P, et al. Coronavirus infections and immune responses. J Med Virol. 2020;92(4):424–432.

Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, et al. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature. 2020;582:289-293.

Zhou H, Fang Y, Xu T, Ni WJ, Shen AZ, Meng XM. Potential therapeutic targets and promising drugs for combating SARS-CoV-2. Br J Pharmacol. 2020;177(14):3147–3161.

Liu Z, Xiao X, Wei X, Li J, Yang J, Tan H, et al. Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS-CoV-2. J Med Virol. 2020:92(6):595–601.

Ghidoli M, Colombo F, Sangiorgio S, Landoni M, Giupponi L, Nielsen E, et al. Food Containing Bioactive Flavonoids and Other Phenolic or Sulfur Phytochemicals With Antiviral Effect: Can We Design a Promising Diet Against COVID-19? Front Nutr. 2021;8:661331.

Chojnacka K, Witek-Krowiak A, Skrzypczak D, Mikula K, Mlynarz P. Phytochemicals containing biologically active polyphenols as an effective agent against Covid-19-inducing coronavirus. J Funct Foods. 2020;73:1041-1046.

Tallei TE, Tumilaar SG, Niode NJ, Wali F, Kepel BJ, Idroes R, et al. Potential of Plant Bioactive Compounds as SARS-CoV-2 Main Protease (Mpro) and Spike (S) Glycoprotein Inhibitors: A Molecular Docking Study. Scientifica. 2020;ID6307457. doi: 10.1155/2020/6307457

Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708–1720.

Cecere TE, Todd SM, Leroith T. Regulatory T cells in arterivirus and coronavirus infections: do they protect against disease or enhance it? Viruses. 2012;4(5):833–846.

Arruda de Souza Monnerat J, Ribeiro de Souza P, Monteiro da Fonseca Cardoso L, Mattos JD, de Souza Rocha G, Frauches Medeiros R. Micronutrients and bioactive compounds in the immunological pathways related to SARS-CoV-2 (adults and elderly). Eur J Nutr. 2021;60:559–579.

Tagde P, Tagde S, Tagde P, Bhattacharya T, Monzur SM, Rahman MH, et al. Nutraceuticals and Herbs in Reducing the Risk and Improving the Treatment of COVID-19 by Targeting SARS-CoV-2. Biomedicines. 2021;9(9):1266.

Shi Y, Wang Y, Shao C, Huang J, Gan J, Huang X, et al. COVID-19 infection: the perspectives on immune responses. Cell Death Differ. 2020;27(5):1451–1454.

Cheng H, Wang Y, Wang GQ. Organ-protective effect of angiotensin-converting enzyme 2 and its effect on the prognosis of COVID-19. J Med Virol. 2020;92:726–730.

Chaudhary R, Garg J, Houghton DE, Murad MH, Kondur A, Chaudhary R, et al. Thromboinflammatory Biomarkers in COVID-19: Systematic Review and Meta-analysis of 17,052 Patients. MCP:IQ&O. 2021;5(2):388–402.

Bivona G, Agnello L, Ciaccio M. Biomarkers for Prognosis and Treatment Response in COVID-19 Patients. Ann Lab Med. 2021;41:540-548.

Vultaggio A, Vivarelli E, Virgili G, Lucenteforte E, Bartoloni A, Nozzoli C, et al. Prompt predicting of early clinical deterioration of moderate-to-severe COVID-19 patients: usefulness of a combined score using IL-6 in a preliminary study. J Allergy Clin Immunol Pract. 2020;8(8):2575-2581.e2.

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497-506.

Herold T, Jurinovic V, Arnreich C, Lipworth BJ, Hellmuth JC, von Bergwelt-Baildon M, et al. Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol. 2020;146(1):128-136.e4.

Liu T, Zhang J, Yang Y, Ma H, Li Z, Zhang J, et al. The role of interleukin-6 in monitoring severe case of coronavirus disease 2019. EMBO Mol Med. 2020;12(7):e12421.

Kermali M, Khalsa RK, Pillai K, Ismail Z, Harky A. The role of biomarkers in diagnosis of COVID-19 - A systematic review. Life Sci. 2020;254:117788.

Akbari H, Tabrizi R, Lankarani KB, Aria H, Vakili S, Asadian F, et al. The role of cytokine profile and lymphocyte subsets in the severity of coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis. Life Sci. 2020;258:118167.

Yip TTC, Chan JWM, Cho WCS, Yip TT, Wang Z, Kwan TL. Protein chip array profiling analysis in patients with severe acute respiratory syndrome identified serum amyloid A protein as a biomarker potentially useful in monitoring the extent of pneumonia. Clin Chem. 2005;51:47-55.

Chaudhary R, Kreutz RP, Bliden KP, Tantry US, Gurbel PA. Personalizing antithrombotic therapy in COVID-19: role of thromboelastography and thromboelastometry. Thromb Haemost. 2020;120(11):1594-1596.

Luo X, Zhou W, Yan X, Guo T, Wang B, Xia H, et al. Prognostic value of C-reactive protein in patients with coronavirus 2019. Clin Infect Dis. 2020;71:2174-2179.

Zhang L, Long Y, Xiao H, Yang J, Toulon P, Zhang Z. Use of D-dimer in oral anticoagulation therapy. Int J Lab Hematol. 2018;40(5):503-507.

Ponti G, Maccaferri M, Ruini C, Tomasi A, Ozben T. Biomarkers associated with COVID-19 disease progression. Crit Rev Clin Lab Sci. 2020;57(6):389-399.

Lippi G, Plebani M. Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis. Clin Chim Acta. 2020;505:190-191.

Huang I, Pranata R, Lim MA, Oehadian A, Alisjahbana B. C-reactive protein, procalcitonin, D-dimer, and ferritin in severe coronavirus disease-2019: a meta-analysis. Ther Adv Respir Dis. 2020;14:1753466620937175.

Han Y, Zhang H, Mu S, Wei W, Jin C, Tong C, et al. Lactate dehydrogenase, an independent risk factor of severe COVID-19 patients: a retrospective and observational study. Aging (Albany NY). 2020;12(12):11245-11258.

Vargas-Vargas M and Cortés-Rojo C. Ferritin levels and COVID-19. Rev Panam Salud Publica. 2020;44:e72.

Aboughdir M, Kirwin T, Abdul Khader AA, Wang B. Prognostic value of cardiovascular biomarkers in COVID-19: a review. Viruses. 2020;12:527.

Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054-1062.

Achan J, Talisuna AO, Erhart A, Yeka A, Tibenderana JK, Baliraine FN, et al. Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. Malar J. 2011;10:144.

Shah RR. Chloroquine and hydroxychloroquine for COVID-19: Perspectives on their failure in repurposing. J Clin Pharm Ther. 2021;46(1):17–27.

Umakanthan S, Sahu P, Ranade AV, Bukelo MM, Rao JS, Abragao-Machado LF, et al. Origin, transmission, diagnosis and management of coronavirus disease 2019 (COVID-19). Postgrad Med J. 2020;96(1142):753–758.

Dudani T, Saraogi A. Use of herbal medicines on coronavirus. Acta Sci Pharm Sci. 2020;11(6):416–419.

Khanna K, Kohli SK, Kaur R, Bhardwaj A, Bhardwaj V, Ohri P, et al. Herbal immune-boosters: substantial warriors of pandemic Covid-19 battle. Phytomedicine. 2021;85:153361.

Di Matteo G, Spano M, Grosso M, Salvo A, Ingallina C, Russo M, et al. Food and COVID-19: preventive/Co-therapeutic strategies explored by current clinical trials and in silico studies. Foods. 2020;9(8):1036.

Stahlmann R, Lode H. Medication for COVID-19-an overview of approaches currently under study. Dtsch Arztebl Int. 2020;117:213–219.

Anand AV, Balamuralikrishnan B, Kaviya M, Bharathi K, Parithathvi A, Arun M, et al. Medicinal Plants, Phytochemicals, and Herbs to Combat Viral Pathogens Including SARS-CoV-2. Molecules. 2021;26(6):1775.

Remali J, Aizat WM. A Review on Plant Bioactive Compounds and their modes of action against Coronavirus infection. Front Pharmacol. 2021;11:589044.

Isaacs CE, Wen GY, Xu W, Jia JH, Rohan L, Corbo C, et al. Epigallocatechin gallate inactivates clinical isolates of herpes simplex virus. Antimicrob Agents Chemother. 2008;52:962–970.

Jena AB, Kanungo N, Nayak V, Chainy GBN, Dandapat J. Catechin and curcumin interact with corona (2019-nCoV/SARSCoV2) viral S protein and ACE2 of human cell membrane: Insights from computational study and implication for intervention. Sci Rep. 2021;11:2043.

Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr H. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet. 2003;361:2045–2046.

Ahmed HM. Ethnomedicinal, phytochemical and pharmacological investigations of Perilla frutescens (L.) Britt Molecules. 2019;24:102.

Ansari WA, Ahamad T, Khan MA, Khan ZA, Khan MF. Luteolin: A Dietary Molecule as Potential Anti-COVID-19 Agent. Res Sq. doi: 10.21203/

Chandramouli V, Niraj SK, Nair KG, Joseph J, Aruni W. Phytomolecules Repurposed as Covid 19 Inhibitors: Opportunity and Challenges. Curr Microbiol. 2021;78:3620-3633.

Wu CY, Jan J-T, Ma S-H, Kuo C-J, Juan H-F, Cheng Y-S, et al. Small molecules targeting severe acute respiratory syndrome human coronavirus. Proc Natl Acad Sci USA. 2004;101(27):10012–10017.

Bahbah EI, Negida A, Nabet MS. Purposing saikosaponins for the treatment of COVID-19. Med Hypotheses. 2020;140:109782.

Yan YM, Shen X, Cao YK, Zhang JJ, Wang Y, Cheng YX. Discovery of anti-2019-nCoV agents from Chinese patent drugs via docking screening. Preprints. 2020;2020020254.

Ho TY, Wu SL, Chen JC, Li CC, Hsiang CY. Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction. Antiviral Res. 2007;74(2):92–101.

Silva T, Oliveira C, Borges F. Caffeic acid derivatives, analogs and applications: a patent review (2009 – 2013). Expert Opin Ther Pat. 2014;24:1257–70.

Weng JR, Lin CS, Lai HC, Lin YP, Wang CY, Tsai YC, et al. Antiviral activity of Sambucus formosana Nakai ethanol extract and related phenolic acid constituents against human coronavirus NL63. Virus Res. 2019;273:197767.

Senthil Kumar KJ, Gokila Vani M, Wang CS, Chen CC, Chen YC, Lu LP, et al. 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. 2020;9(6):770.

Yi L, Li Z, Yuan K, Qu X, Chen J, Wang G, et al. Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells. J Virol. 2004;78:11334–11339.

Basu A, Sarkar A, Maulik U. Molecular docking study of potential phytochemicals and their effects on the complex of SARS-CoV2 spike protein and human ACE2. Sci Rep. 2020;10(1):17699.

Ye M, Luo G, Ye D, She M, Sun N, Lu Y-J, et al. Network pharmacology, molecular docking integrated surface plasmon resonance technology reveals the mechanism of Toujie Quwen Granules against coronavirus disease 2019 pneumonia. Phytomedicine. 2021;85:153401.

Chen F, Chan KH, Jiang Y, Kao RYT, Lu HT, Fan KW, et al. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J Clin Virol. 2004;31:69–75.

Simmons G, Gosalia DN, Rennekamp AJ, Reeves JD, Diamond SL, Bateset P. Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proc Natl Acad Sci USA. 2005;102:11876–11881.

Tang TT, Lv LL, Pan MM, Wen Y, Wang B, Li ZL, et al. Hydroxychloroquine attenuates renal ischemia/reperfusion injury by inhibiting cathepsin mediated NLRP3 inflammasome activation. Cell Death Dis. 2018;9:351.

Zhou YX, Xin HL, Rahman K, Wang SJ, Peng C, Zhang H. Portulaca oleracea L.: a review of phytochemistry and pharmacological effects. Biomed Res Int. 2015;925631. doi: 10.1155/2015/925631

Wang SQ, Du QS, Zhao K, Li AX, Wei DQ, Chou KC. Virtual screening for finding natural inhibitor against cathepsin-L for SARS therapy. Amino Acids. 2007;33(1):129–135.

Milewska A, Nowak P, Owczarek K, Szczepanski A, Zarebski M, Hoang A, et al. Entry of Human Coronavirus NL63 into the Cell J Virol. 2018;92(3):e01933-17.

Zhuang M, Jiang H, Suzuki Y, Li X, Xiao P, Tanaka T, et al. Procyanidins and butanol extract of Cinnamomi Cortex inhibit SARS-CoV infection. Antiviral Res. 2009;82(1):73–81.

Gao Y, Yan L, Huang Y, Liu F, Zhao Y, Cao L, et al. Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science. 2020;368(6492):779-782.

El-Aziz Abd NM, Mohamed GS, Awad OME, El-Sohaimy SA. Inhibition of COVID-19 RNA-Dependent RNA Polymerase by Natural Bioactive Compounds: Molecular Docking Analysis. Preprint. doi: 10.21203/RS.3.RS-25850/V1.

Review articles