The Potential of Anti-coronavirus Plant Secondary Metabolites in COVID-19 Drug Discovery as an Alternative to Repurposed Drugs: A Review

Zahra Alipour; Somayeh Zarezadeh; Ali Akbar Ghotbi-Ravandi

doi:10.1055/a-2209-6357

Planta Medica, Table of Contents

Planta Med 2024; 90(03): 172-203
DOI: 10.1055/a-2209-6357

Biological and Pharmacological Activity

Reviews

The Potential of Anti-coronavirus Plant Secondary Metabolites in COVID-19 Drug Discovery as an Alternative to Repurposed Drugs: A Review

Authors

Zahra Alipour

Department of Plant Sciences and Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
Somayeh Zarezadeh

Department of Plant Sciences and Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
Ali Akbar Ghotbi-Ravandi

Department of Plant Sciences and Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran

Abstract

In early 2020, a global pandemic was announced due to the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known to cause COVID-19. Despite worldwide efforts, there are only limited options regarding antiviral drug treatments for COVID-19. Although vaccines are now available, issues such as declining efficacy against different SARS-CoV-2 variants and the aging of vaccine-induced immunity highlight the importance of finding more antiviral drugs as a second line of defense against the disease. Drug repurposing has been used to rapidly find COVID-19 therapeutic options. Due to the lack of clinical evidence for the therapeutic benefits and certain serious side effects of repurposed antivirals, the search for an antiviral drug against SARS-CoV-2 with fewer side effects continues. In recent years, numerous studies have included antiviral chemicals from a variety of plant species. A better knowledge of the possible antiviral natural products and their mechanism against SARS-CoV-2 will help to develop stronger and more targeted direct-acting antiviral agents. The aim of the present study was to compile the current data on potential plant metabolites that can be investigated in COVID-19 drug discovery and development. This review represents a collection of plant secondary metabolites and their mode of action against SARS-CoV and SARS-CoV-2.

Key words

SARS-CoV-2 - antivirals - phytochemicals - natural products - medicinal plants - alternative medicine

Full Text

References

References
1 COVID-19 statistics. Accessed 03.01.2023 at: https://www.worldometers.info/coronavirus
2 Yang H, Bartlam M, Rao Z. Drug design targeting the main protease, the Achillesʼ heel of coronaviruses. Curr Pharm Des 2006; 12: 4573-4590
3 Mousavizadeh L, Ghasemi S. Genotype and phenotype of COVID-19: Their roles in pathogenesis. J Microbiol Immunol Infect 2021; 54: 159-163
4 Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, Guo L, Guo R, Chen T, Hu J, Xiang Z, Mu Z, Chen X, Chen J, Hu K, Jin Q, Wang J, Qian Z. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun 2020; 11: 1620
5 Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res 2020; 176: 104742
6 Liang Y, Wang ML, Chien CS, Yarmishyn AA, Yang YP, Lai WY, Luo YH, Lin YT, Chen YJ, Chang PC, Chiou SH. Highlight of immune pathogenic response and hematopathologic effect in SARS-CoV, MERS-CoV, and SARS-Cov-2 infection. Front Immunol 2020; 11: 1022
7 Chen B, Tian EK, He B, Tian L, Han R, Wang S, Xiang Q, Zhang S, El Arnaout T, Cheng W. Overview of lethal human coronaviruses. Signal Transduct Target Ther 2020; 5: 89
8 Xu J, Zhao S, Teng T, Abdalla AE, Zhu W, Xie L, Wang Y, Guo X. Systematic comparison of two animal-to-human transmitted human coronaviruses: SARS-CoV-2 and SARS-CoV. Viruses 2020; 12: 244
9 Zhou Y, Hou Y, Shen J, Huang Y, Martin W, Cheng F. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov 2020; 6: 14
10 Lu H. Drug treatment options for the 2019-new coronavirus (2019-nCoV). Biosci Trends 2020; 14: 69-71
11 Cyranoski D. This scientist hopes to test coronavirus drugs on animals in locked-down Wuhan. Nature 2020; 577: 607
12 Cohen J. New coronavirus threat galvanizes scientists. Science 2020; 367: 492-493
13 Li G, Hilgenfeld R, Whitley R, De Clercq E. Therapeutic strategies for COVID-19: Progress and lessons learned. Nat Rev Drug Discov 2023; 22: 449-475
14 Yang H, Rao Z. Structural biology of SARS-CoV-2 and implications for therapeutic development. Nat Rev Microbiol 2021; 19: 685-700
15 Chen Z, Du R, Galvan Achi JM, Rong L, Cui Q. SARS-CoV-2 cell entry and targeted antiviral development. Acta Pharm Sin B 2021; 11: 3879-3888
16 Muralidar S, Gopal G, Visaga Ambi S. Targeting the viral-entry facilitators of SARS-CoV-2 as a therapeutic strategy in COVID-19. J Med Virol 2021; 93: 5260-5276
17 Tharappel AM, Samrat SK, Li Z, Li H. Targeting crucial host factors of SARS-CoV-2. ACS Infect Dis 2020; 6: 2844-2865
18 Sacco MD, Ma C, Lagarias P, Gao A, Townsend JA, Meng X, Dube P, Zhang X, Hu Y, Kitamura N, Hurst B, Tarbet B, Marty MT, Kolocouris A, Xiang Y, Chen Y, Wang J. Structure and inhibition of the SARS-CoV-2 main protease reveal strategy for developing dual inhibitors against M(pro) and cathepsin L. Sci Adv 2020; 6: eabe0751
19 Anirudhan V, Lee H, Cheng H, Cooper L, Rong L. Targeting SARS-CoV-2 viral proteases as a therapeutic strategy to treat COVID-19. J Med Virol 2021; 93: 2722-2734
20 Xia Z, Sacco MD, Ma C, Townsend JA, Kitamura N, Hu Y, Ba M, Szeto T, Zhang X, Meng X, Zhang F, Xiang Y, Marty MT, Chen Y, Wang J. Discovery of SARS-CoV-2 papain-like protease inhibitors through a combination of high-throughput screening and FlipGFP-based reporter assay. ACS Cent Sci 2021; 7: 1245-1260
21 Wang Y, Anirudhan V, Du R, Cui Q, Rong L. RNA-dependent RNA polymerase of SARS-CoV-2 as a therapeutic target. J Med Virol 2021; 93: 300-310
22 Niknam Z, Jafari A, Golchin A, Danesh Pouya F, Nemati M, Rezaei-Tavirani M, Rasmi Y. Potential therapeutic options for COVID-19: An update on current evidence. Eur J Med Res 2022; 27: 1-15
23 Norrie JD. Remdesivir for COVID-19: challenges of underpowered studies. Lancet 2020; 395: 1525-1527
24 Grundeis F, Ansems K, Dahms K, Thieme V, Metzendorf MI, Skoetz N, Benstoem C, Mikolajewska A, Griesel M, Fichtner F, Stegemann M. Remdesivir for the treatment of COVID-19. Cochrane Database Syst Rev 2023; (01) CD014962
25 Tasavon Gholamhoseini M, Yazdi-Feyzabadi V, Goudarzi R, Mehrolhassani MH. Safety and efficacy of remdesivir for the treatment of COVID-19: A systematic review and meta-analysis. J Pharm Pharm Sci 2021; 24: 237-245
26 Patel TK, Patel PB, Barvaliya M, Saurabh MK, Bhalla HL, Khosla PP. Efficacy and safety of lopinavir-ritonavir in COVID-19: A systematic review of randomized controlled trials. J Infect Public Health 2021; 14: 740-748
27 Samaee H, Mohsenzadegan M, Ala S, Maroufi SS, Moradimajd P. Tocilizumab for treatment patients with COVID-19: recommended medication for novel disease. Int Immunopharmacol 2020; 89: 107018
28 Almeida PRL, Person OC, Puga MEDS, Giusti MF, Pinto ACPN, Rocha AP, Atallah ÁN. Effectiveness and safety of tocilizumab for COVID-19: A systematic review and meta-analysis of randomized clinical trials. Sao Paulo Med J 2022; 141: 168-176
29 Sarhan NM, Warda AEA, Ibrahim HSG, Schaalan MF, Fathy SM. Evaluation of infliximab/tocilizumab versus tocilizumab among COVID-19 patients with cytokine storm syndrome. Sci Rep 2023; 13: 6456
30 Richardson PJ, Robinson BWS, Smith DP, Stebbing J. The AI-assisted identification and clinical efficacy of baricitinib in the treatment of COVID-19. Vaccines 2022; 10: 951
31 Jorgensen SCJ, Tse CLY, Burry L, Dresser LD. Baricitinib: A review of pharmacology, safety, and emerging clinical experience in COVID-19. Pharmacotherapy 2020; 40: 843-856
32 Hashemian SMR, Sheida A, Taghizadieh M, Memar MY, Hamblin MR, Bannazadeh Baghi H, Sadri Nahand J, Asemi Z, Mirzaei H. Paxlovid (nirmatrelvir/ritonavir): a new approach to COVID-19 therapy?. Biomed Pharmacother 2023; 162: 114367
33 Kimata M, Watanabe A, Yanagida Y, Kinoshita D, Maekawa S. Safety and effectiveness of molnupiravir (LAGEVRIO^®) cpsules in Japanese patients with COVID-19: interim report of post-marketing surveillance in Japan. Infect Dis Ther 2023; 12: 1119-1136
34 Yip AJW, Low ZY, Chow VTK, Lal SK. Repurposing molnupiravir for COVID-19: The mechanisms of antiviral activity. Viruses 2022; 14: 1345
35 Khani E, Shahrabi M, Rezaei H, Pourkarim F, Afsharirad H, Solduzian M. Current evidence on the use of anakinra in COVID-19. Int Immunopharmacol 2022; 111: 109075
36 Elmekaty EZI, Maklad A, Abouelhassan R, Munir W, Ibrahim MIM, Nair A, Alibrahim R, Iqbal F, Al Bishawi A, Abdelmajid A, Aboukamar M, Hadi HA, Khattab MA, Al Soub H, Al Maslamani M. Evaluation of anakinra in the management of patients with COVID-19 infection: A randomized clinical trial. Front Microbiol 2023; 14: 1098703
37 Harris E. FDA approves vilobelimab for emergency use in hospitalized adults. JAMA 2023; 329: 1544
38 Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, Lopez de Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short WR, Touloumi G, Lye DC, Ohmagari N, Oh MD, Ruiz-Palacios GM, Benfield T, Fätkenheuer G, Kortepeter MG, Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski M, Osinusi A, Nayak S, Lane HC. ACTT-1 Study Group Members. Remdesivir for the treatment of COVID – final report. N Engl J Med 2020; 383: 1813-1826
39 Humeniuk R, Mathias A, Cao H, Osinusi A, Shen G, Chng E, Ling J, Vu A, German P. Safety, tolerability, and pharmacokinetics of remdesivir, an antiviral for treatment of COVID-19, in Healthy Subjects. Clin Transl Sci 2020; 13: 896-906
40 Elsawah HK, Elsokary MA, Abdallah MS, ElShafie AH. Efficacy and safety of remdesivir in hospitalized Covid-19 patients: Systematic review and meta-analysis including network meta-analysis. Rev Med Virol 2021; 31: e2187
41 Zampino R, Mele F, Florio LL, Bertolino L, Andini R, Galdo M, De Rosa R, Corcione A, Durante-Mangoni E. Liver injury in remdesivir-treated COVID-19 patients. Hepatol Int 2020; 14: 881-883
42 Montastruc F, Thuriot S, Durrieu G. Hepatic disorders with the use of remdesivir for coronavirus 2019. Clin Gastroenterol Hepatol 2020; 18: 2835-2836
43 Hu K, Guan WJ, Bi Y, Zhang W, Li L, Zhang B, Liu Q, Song Y, Li X, Duan Z, Zheng Q, Yang Z, Liang J, Han M, Ruan L, Wu C, Zhang Y, Jia ZH, Zhong NS. Efficacy and safety of Lianhuaqingwen capsules, a repurposed Chinese herb, in patients with coronavirus disease 2019: A multicenter, prospective, randomized controlled trial. Phytomedicine 2021; 85: 153242
44 Chantrill BH, Coulthard CE, Dickinson L, Inkley GW, Morris W, Pyle AH. The action of plant extracts on a bacteriophage of Pseudomonas pyocyanea and on influenza A virus. J Gen Microbiol 1952; 6: 74-84
45 Denaro M, Smeriglio A, Barreca D, De Francesco C, Occhiuto C, Milano G, Trombetta D. Antiviral activity of plants and their isolated bioactive compounds: An update. Phyther Res 2020; 34: 742-768
46 Ali SI, Sheikh WM, Rather MA, Venkatesalu V, Muzamil Bashir S, Nabi SU. Medicinal plants: Treasure for antiviral drug discovery. Phyther Res 2021; 35: 3447-3483
47 Ma L, Yao L. Antiviral effects of plant-derived essential oils and their components: An updated review. Molecules 2020; 25: 1-13
48 Guerra Y, Celi D, Cueva P, Perez-Castillo Y, Giampieri F, Alvarez-Suarez JM, Tejera E. Critical review of plant-derived compounds as possible inhibitors of SARS-CoV – 2 proteases: a comparison with experimentally validated molecules. ACS Omega 2022; 7: 44542-44555
49 Yuvejwattana S. Thailand clears use of herbal medicine for COVID-19 treatment. Accessed January 3, 2023 at: https://www.bloomberg.com/news/articles/2020-12-30/thailand-clears-use-of-herbal-medicine-for-covid-19-treatment
50 Wink M. Plant secondary metabolites modulate insect behavior-steps toward addiction?. Front Physiol 2018; 9: 1-9
51 Isah T. Stress and defense responses in plant secondary metabolites production. Biol Res 2019; 52: 39
52 Jan R, Asaf S, Numan M, Lubna. Kim KM. Plant secondary metabolite biosynthesis and transcriptional regulation in response to biotic and abiotic stress conditions. Agronomy 2021; 11: 1-31
53 Johnson M. Wuhan 2019 novel coronavirus – 2019-nCoV. Mater Methods 2020; 10: 1-5
54 Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol 2020; 5: 536-544
55 Wang MY, Zhao R, Gao LJ, Gao XF, Wang DP, Cao JM. SARS-CoV-2: Structure, biology, and structure-based therapeutics development. Front Cell Infect Microbiol 2020; 10: 1-17
56 Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, Wang W, Song H, Huang B, Zhu N, Bi Y, Ma X, Zhan F, Wang L, Hu T, Zhou H, Hu Z, Zhou W, Zhao L, Chen J, Meng Y, Wang J, Lin Y, Yuan J, Xie Z, Ma J, Liu WJ, Wang D, Xu W, Holmes EC, Gao GF, Wu G, Chen W, Shi W, Tan W. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 2020; 395: 565-574
57 Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579: 270-273
58 Yu F, Du L, Ojcius DM, Pan C, Jiang S. Measures for diagnosing and treating infections by a novel coronavirus responsible for a pneumonia outbreak originating in Wuhan, China. Microbes Infect 2020; 22: 74-79
59 Adhikari SP, Meng S, Wu YJ, Mao YP, Ye RX, Wang QZ, Sun C, Sylvia S, Rozelle S, Raat H, Zhou H. Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: A scoping review. Infect Dis Poverty 2020; 9: 29
60 van Boheemen S, de Graaf M, Lauber C, Bestebroer TM, Raj VS, Zaki AM, Osterhaus ADME, Haagmans BL, Gorbalenya AE, Snijder EJ, Fouchier RAM. Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans. MBio 2012; 3: e00473-12
61 Snijder EJ, Bredenbeek PJ, Dobbe JC, Thiel V, Ziebuhr J, Poon LLM, Guan Y, Rozanov M, Spaan WJM, Gorbalenya AE. Unique and conserved features of genome and proteome of SARS-coronavirus, an early split-off from the coronavirus group 2 lineage. J Mol Biol 2003; 331: 991-1004
62 Gorbalenya AE, Baker SC, Baric RS, de Groot RJ, Drosten C, Gulyaeva AA, Haagmans BL, Lauber C, Leontovich AM, Neuman BW, Penzar D, Perlman S, Poon LLM, Samborskiy DV, Sidorov IA, Sola I, Ziebuhr J. The species severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol 2020; 5: 536-544
63 Fontanet A, Autran B, Lina B, Kieny MP, Karim SSA, Sridhar D. SARS-CoV-2 variants and ending the COVID-19 pandemic. Lancet 2021; 397: 952-954
64 Karim SSA, Karim QA. Omicron SARS-CoV-2 variant: A new chapter in the COVID-19 pandemic. Lancet 2021; 398: 2126-2128
65 Sternberg A, Naujokat C. Structural features of coronavirus SARS-CoV-2 spike protein: Targets for vaccination. Life Sci 2020; 257: 118056
66 Hu B, Guo H, Zhou P, Shi ZL. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol 2021; 19: 141-154
67 Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020; 382: 727-733
68 Yadav R, Chaudhary JK, Jain N, Chaudhary PK, Khanra S, Dhamija P, Sharma A, Kumar A, Handu S. Role of structural and non-structural proteins and therapeutic targets of SARS-CoV-2 for COVID-19. Cells 2021; 10: 821
69 Chan JFW, Kok KH, Zhu Z, Chu H, To KKW, Yuan S, Yuen KY. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microbes Infect 2020; 9: 221-236
70 Chakravarti R, Singh R, Ghosh A, Dey D, Sharma P, Velayutham R, Roy S, Ghosh D. A review on potential of natural products in the management of COVID-19. RSC Adv 2021; 11: 16711-16735
71 Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens T, Herrler G, Wu NH, Nitsche A, Müller M, Drosten C, Pöhlmann S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181: 271-280
72 Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart R, Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res 2000; 87: E1-9
73 Chen YW, Lee MS, Lucht A, Chou FP, Huang W, Havighurst T, Kim K, Wang JK, Antalis T, Johnson M, Lin CY. TMPRSS2, a serine protease expressed in the prostate on the apical surface of luminal epithelial cells and released into semen in prostasomes, is misregulated in prostate cancer cells. Am J Pathol 2010; 176: 2986-2996
74 Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pöhlmann S. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the SARS-coronavirus spike-protein. J Virol 2013; 88: 1293-1307
75 Park Y. TMPRSS2 (transmembrane protease, serine 2). Atlas Genet Cytogenet Oncol Haematol 2011; 14: 1163-1165
76 Vaarala M, Porvari K, Kellokumpu S, Kyllönen A, Vihko P. Expression of transmembrane serine protease TMPRSS2 in mouse and human tissues. J Pathol 2001; 193: 134-140
77 Luo H, Tie L, Cao M, Hunter A, Pabst T, Du J, Field R, Li Y, Wang W. Cathepsin L causes proteolytic cleavage of CHO expressed proteins during processing and storage: identification, characterization, and mitigation. Biotechnol Prog 2018; 35: e2732
78 Anderson E, Molloy S, Jean F, Fei H, Shimamura S. The ordered and compartment-specific autoproteolytic removal of the furin intramolecular chaperone is required for enzyme activation. J Biol Chem 2002; 277: 12879-12890
79 Bisht N, Singh BK. Role of computer aided drug design in drug development and drug discovery. Int J Pharm Sci Res 2018; 9: 1405-1415
80 Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31: 455-461
81 Rakib A, Nain Z, Sami SA, Mahmud S, Islam A, Ahmed S, Siddiqui ABF, Babu SMOF, Hossain P, Shahriar A, Nainu F, Emran TB, Simal-Gandara J. A molecular modelling approach for identifying antiviral selenium-containing heterocyclic compounds that inhibit the main protease of SARS-CoV-2: An in silico investigation. Brief Bioinform 2021; 22: 1476-1498
82 Rani I, Kalsi A, Kaur G, Sharma P, Gupta S, Gautam RK, Chopra H, Bibi S, Ahmad SU, Singh I, Dhawan M, Emran TB. Modern drug discovery applications for the identification of novel candidates for COVID-19 infections. Ann Med Surg 2022; 80: 104125
83 Yuriev E, Agostino M, Ramsland PA. Challenges and advances in computational docking: 2009 in review. J Mol Recognit 2011; 24: 149-164
84 Ren J, He Y, Chen W, Chen T, Wang G, Wang Z, Xu Z, Luo X, Zhu W, Jiang H, Shen J, Xu Y. Thermodynamic and structural characterization of halogen bonding in protein–ligand interactions: A case study of PDE5 and its inhibitors. J Med Chem 2014; 57: 3588-3593
85 Spyrakis F, Cavasotto CN. Open challenges in structure-based virtual screening: Receptor modeling, target flexibility consideration and active site water molecules description. Arch Biochem Biophys 2015; 583: 105-119
86 Sethi A, Joshi K, Sasikala K, Alvala M. Molecular Docking in Modern Drug Discovery: Principles and Recent Applications. In: Gaitonde V, Karmakar P, Trivedi A, eds. Drug Discovery and Development – New Advances. IntechOpen. 2020: 13
87 Shoichet BK, Leach AR, Kuntz ID. Ligand solvation in molecular docking. Proteins 1999; 34: 4-16
88 Gupta Y, Savytskyi OV, Coban M, Venugopal A, Pleqi V, Weber CA, Chitale R, Durvasula R, Hopkins C, Kempaiah P, Caulfield TR. Protein structure-based in-silico approaches to drug discovery: Guide to COVID-19 therapeutics. Mol Aspects Med 2023; 91: 101151
89 Freddolino PL, Harrison CB, Liu Y, Schulten K. Challenges in protein-folding simulations. Nat Phys 2010; 6: 751-758
90 Liu X, Shi D, Zhou S, Liu H, Liu H, Yao X. Molecular dynamics simulations and novel drug discovery. Expert Opin Drug Discov 2018; 13: 23-37
91 De Vivo M, Masetti M, Bottegoni G, Cavalli A. Role of molecular dynamics and related methods in drug discovery. J Med Chem 2016; 59: 4035-4061
92 Salomon-Ferrer R, Götz AW, Poole D, Le Grand S, Walker RC. Routine microsecond molecular dynamics simulations with AMBER on GPUs. 2. Explicit Solvent Particle Mesh Ewald. J Chem Theory Comput 2013; 9: 3878-3888
93 Filipe HAL, Loura LMS. Molecular dynamics simulations: Advances and applications. Molecules 2022; 27: 37-47
94 Kumar A, Choudhir G, Shukla SK, Sharma M, Tyagi P, Bhushan A, Rathore M. Identification of phytochemical inhibitors against main protease of COVID-19 using molecular modeling approaches. J Biomol Struct Dyn 2021; 39: 3760-3770
95 Muratov EN, Amaro R, Andrade CH, Brown N, Ekins S, Fourches D, Isayev O, Kozakov D, Medina-Franco JL, Merz KM, Oprea TI, Poroikov V, Schneider G, Todd MH, Varnek A, Winkler DA, Zakharov AV, Cherkasov A, Tropsha A. A critical overview of computational approaches employed for COVID-19 drug discovery. Chem Soc Rev 2021; 50: 9121-9151
96 Jantan I, Arshad L, Septama AW, Haque MA, Mohamed-Hussein ZA, Govender NT. Antiviral effects of phytochemicals against severe acute respiratory syndrome coronavirus 2 and their mechanisms of action: A review. Phytother Res 2023; 37: 1036-1056
97 Lamers MM, van der Vaart J, Knoops K, Riesebosch S, Breugem TI, Mykytyn AZ, Beumer J, Schipper D, Bezstarosti K, Koopman CD, Groen N, Ravelli RBG, Duimel HQ, Demmers JAA, Verjans GMGM, Koopmans MPG, Muraro MJ, Peters PJ, Clevers H, Haagmans BL. An organoid-derived bronchioalveolar model for SARS-CoV-2 infection of human alveolar type II-like cells. EMBO J 2021; 40: e105912
98 Bukowy-Bieryłło Z. Long-term differentiating primary human airway epithelial cell cultures: How far are we?. Cell Commun Signal 2021; 19: 63
99 Ramirez S, Fernandez-Antunez C, Galli A, Underwood A, Pham LV, Ryberg LA, Feng S, Pedersen MS, Mikkelsen LS, Belouzard S, Dubuisson J, Sølund C, Weis N, Gottwein JM, Fahnøe U, Bukh J. Overcoming culture restriction for SARS-CoV-2 in human cells facilitates the screening of compounds inhibiting viral replication. Antimicrob Agents Chemother 2021; 65: e0009721
100 Lamers MM, Haagmans BL. SARS-CoV-2 pathogenesis. Nat Rev Microbiol 2022; 20: 270-284
101 Ranga A, Gjorevski N, Lutolf MP. Drug discovery through stem cell-based organoid models. Adv Drug Deliv Rev 2014; 69 – 70: 19-28
102 Takayama K. In vitro and animal models for SARS-CoV-2 research. Trends Pharmacol Sci 2020; 41: 513-517
103 Morales-Paredes CA, Rodríguez-Díaz JM, Boluda-Botella N. Pharmaceutical compounds used in the COVID-19 pandemic: A review of their presence in water and treatment techniques for their elimination. Sci Total Environ 2022; 814: 152691
104 Khan T, Khan MA, Mashwani ZUR, Ullah N, Nadhman A. Therapeutic potential of medicinal plants against COVID-19: The role of antiviral medicinal metabolites. Biocatal Agric Biotechnol 2021; 31: 101890
105 Deng W, Xu Y, Kong Q, Xue J, Yu P, Liu J, Lv Q, Li F, Wei Q, Bao L. Therapeutic efficacy of pudilan xiaoyan oral liquid (PDL) for COVID-19 in vitro and in vivo . Signal Transduct Target Ther 2020; 5: 2-4
106 Song J, Zhang L, Xu Y, Yang D, Yang S, Zhang W, Wang J, Tian S, Yang S, Yuan T, Liu A, Lv Q, Li F, Liu H, Hou B, Peng X, Lu Y, Du G. The comprehensive study on the therapeutic effects of baicalein for the treatment of COVID-19 in vivo and in vitro . Biochem Pharmacol 2021; 183: 114302
107 Giordano D, Facchiano A, Carbone V. food plant secondary metabolites antiviral activity and their possible roles in SARS-CoV-2 treatment: An overview. Molecules 2023; 28: 2470
108 Ahmad R, Srivastava S, Ghosh S, Khare SK. Phytochemical delivery through nanocarriers: A review. Colloids Surf B Biointerfaces 2021; 197: 111389
109 Ben-Shabat S, Yarmolinsky L, Porat D, Dahan A. Antiviral effect of phytochemicals from medicinal plants: Applications and drug delivery strategies. Drug Deliv Transl Res 2020; 10: 354-367
110 Hartmann T. From waste products to ecochemicals: Fifty years research of plant secondary metabolism. Phytochemistry 2007; 68: 2831-2846
111 Balandrin MF, Klocke JA, Wurtele ES, Bollinger WH. Natural plant chemicals: Sources of industrial and medicinal materials. Science 1985; 228: 1154-1160
112 Janzen DH. Secondary Plant Products. In: Bell EA, Charlwood BV, eds. Encyclopedia of Plant Physiology, New Series. Environ Conserv. Cambridge: Cambridge University Press; 1981: 79
113 Ebenezer KS, Manivannan R, Punniyamoorthy A, Tamilselvan C. Plant secondary metabolites of antiviral properties a rich medicinal source for drug discovery: a mini review. J Drug Deliv Ther 2019; 9: 161-167
114 Bhuiyan FR, Howlader S, Raihan T, Hasan M. Plants metabolites: Possibility of natural therapeutics against the COVID-19 pandemic. Front Med 2020; 7: 1-26
115 Hussein RA, El-Anssary AA. Plants secondary metabolites: The key drivers of the pharmacological actions of medicinal plants. In: Builders PF, ed. Herbal Medicine. London: Intechopen. 2018
116 Carletti G, Nervo G, Cattivelli L. Flavonoids and melanins: A common strategy across two kingdoms. Int J Biol Sci 2014; 10: 1159-1170
117 Zakaryan H, Arabyan E, Oo A, Zandi K. Flavonoids: Promising natural compounds against viral infections. Arch Virol 2017; 162: 2539-2551
118 Ferraz C, Teixeira de Carvalho T, Manchope M, Artero N, Rasquel-Oliveira F, Fattori V, Casagrande R, Verri W. Therapeutic potential of flavonoids in pain and inflammation: mechanisms of action, pre-clinical and clinical data, and pharmaceutical development. Molecules 2020;
119 Anand AV, Balamuralikrishnan B, Kaviya M, Bharathi K, Parithathvi A, Arun M, Senthilkumar N, Velayuthaprabhu S, Saradhadevi M, Al-Dhabi NA, Arasu MV, Yatoo MI, Tiwari R, Dhama K. Medicinal plants, phytochemicals, and herbs to combat viral pathogens including SARS-CoV-2. Molecules 2021; 26: 1-28
120 Ogbole O, Akinleye T, Segun P, Faleye T, Adeniji A. In vitro antiviral activity of twenty-seven medicinal plant extracts from Southwest Nigeria against three serotypes of echoviruses. Virol J 2018; 15: 110
121 Andres A, Donovan S, Kuhlenschmidt M. Current Topics Soy isoflavones and virus infections. J Nutr Biochem 2009; 20: 563-569
122 Ngwa W, Kumar R, Thompson D, Lyerly W, Moore R, Reid TE, Lowe H, Toyang N. Potential of flavonoid-inspired phytomedicines against COVID-19. Molecules 2020; 25: 2707
123 Palit P, Mukhopadhyay A, Chattopadhyay D. Phyto-pharmacological perspective of Silymarin: A potential prophylactic or therapeutic agent for COVID-19, based on its promising immunomodulatory, anti-coagulant and anti-viral property. Phytother Res 2021; 35: 4246-4257
124 Gillessen A, Schmidt HHJ. Silymarin as supportive treatment in liver diseases: A narrative review. Adv Ther 2020; 37: 1279-1301
125 Hanafy NAN, El-Kemary MA. Silymarin/curcumin loaded albumin nanoparticles coated by chitosan as muco-inhalable delivery system observing anti-inflammatory and anti COVID-19 characterizations in oleic acid triggered lung injury and in vitro COVID-19 experiment. Int J Biol Macromol 2022; 198: 101-110
126 ClinicalTrials.gov. Silymarin in COVID-19 Pneumonia (SCOPE), NCT04394208. Accessed September 22, 2022 at: https://classic.clinicaltrials.gov/ct2/show/NCT04394208
127 Thilakarathna SH, Rupasinghe HPV. Flavonoid bioavailability and attempts for bioavailability enhancement. Nutrients 2013; 5: 3367-3387
128 Ross JA, Kasum CM. Dietary flavonoids: Bioavailability, metabolic effects, and safety. Annu Rev Nutr 2002; 22: 19-34
129 Seguin J, Brullé L, Boyer R, Lu YM, Ramos Romano M, Touil YS, Scherman D, Bessodes M, Mignet N, Chabot GG. Liposomal encapsulation of the natural flavonoid fisetin improves bioavailability and antitumor efficacy. Int J Pharm 2013; 444: 146-154
130 Zobeiri M, Belwal T, Parvizi F, Naseri R, Farzaei MH, Nabavi SF, Sureda A, Nabavi SM. Naringenin and its nano-formulations for fatty liver: Cellular modes of action and clinical perspective. Curr Pharm Biotechnol 2018; 19: 196-205
131 David A, Arulmoli R, Parasuraman S. Overviews of biological importance of quercetin: A bioactive flavonoid. Pharmacogn Rev 2016; 10: 84
132 Chen L, Li J, Luo C, Liu H, Xu W, Chen G, Liew OW, Zhu W, Puah C, Shen X, Jiang H. Binding interaction of quercetin-3-β-galactoside and its synthetic derivatives with SARS-CoV 3CLpro: Structure-activity relationship studies reveal salient pharmacophore features. Bioorg Med Chem 2007; 14: 8295-8306
133 Nguyen TTH, Woo HJ, Kang HK, Nguyen V, Kim YM, Kim DW, Ahn SA, Xia Y, Kim D. Flavonoid-mediated inhibition of SARS coronavirus 3C-like protease expressed in Pichia pastoris . Biotechnol Lett 2012; 34: 831-838
134 Zhang D, Wu K, Zhang X, Deng S, Peng B. In silico screening of Chinese herbal medicines with the potential to directly inhibit 2019 novel coronavirus. J Integr Med 2020; 18: 152-158
135 Sampangi-Ramaiah M, Vishwakarma R, Umashaanker R. Molecular docking analysis of selected natural products from plants for inhibition of SARS-CoV-2 main protease. Curr Sci 2020; 118: 1087-1092
136 Verma S, Pandey AK. Factual insights of the allosteric inhibition mechanism of SARS-CoV-2 main protease by quercetin: an in silico analysis. 3 Biotech 2021; 11: 67
137 Cherrak SA, Merzouk H, Mokhtari-Soulimane N. Potential bioactive glycosylated flavonoids as SARS-CoV-2 main protease inhibitors: A molecular docking and simulation studies. PLoS One 2020; 15: 1-14
138 Hiremath S, Kumar H, Nandan M, Muttappagol M, Shankarappa KS, Venkataravanappa V, Basha C, Reddy CNL. In silico docking analysis revealed the potential of phytochemicals present in Phyllanthus amarus and Andrographis paniculata, used in Ayurveda medicine in inhibiting SARS-CoV-2. 3 Biotech 2021; 11: 44
139 Joshi T, Joshi T, Sharma P, Mathpal S, Pundir H, Bhatt V, Chandra S. In silico screening of natural compounds against COVID-19 by targeting Mpro and ACE2 using molecular docking. Eur Rev Med Pharmacol Sci 2020; 24: 4529-4536
140 Sekiou O, Bouziane I, Frissou N, Bouslama Z, Honcharova O, Djemel A, Benselhoub A. In-Silico identification of potent inhibitors of COVID-19 main protease (Mpro) from natural products. Int J Biochem Physiol 2021; 5: 000189
141 Alimohammadi SZM, Hasani KM, Malekahmadi M, Persad E, Heshmati J. The effect of quercetin supplementation on clinical outcomes in COVID-19 patients: a systematic review and meta-analysis. Food Sci Nutr 2023;
142 Gangarapu K, Loganathan K, Devi MSS, Parameswaran S, Kanakavalli K, Kumar KM, Kumar D. In Silico computational screening of Kabasura Kudineer – official Siddha formulation and JACOM against SARS-CoV-2 spike protein. J Ayurveda Integr Med 2020; 13: 100324
143 Vijayakumar B, Ramesh D, Joji A, Jayachandra Prakasan J, Kannan T. In silico pharmacokinetic and molecular docking studies of natural flavonoids and synthetic indole chalcones against essential proteins of SARS-CoV-2. Eur J Pharmacol 2020; 886: 173448
144 Liu X, Raghuvanshi R, Ceylan FD, Bolling BW. Quercetin and its metabolites inhibit recombinant human angiotensin-converting enzyme 2 (ACE2) activity. J Agric Food Chem 2020; 68: 13982-13989
145 da Silva JKR, Figueiredo PLB, Byler KG, Setzer WN. Essential oils as antiviral agents. Potential of essential oils to treat SARS−COV−2 infection: An in−silico investigation. Int J Mol Sci 2020; 21: 1-37
146 Pandey P, Rane JS, Chatterjee A, Kumar A, Khan R, Prakash A, Ray S. Targeting SARS-CoV-2 spike protein of COVID-19 with naturally occurring phytochemicals: An in silico study for drug development. J Biomol Struct Dyn 2020; 39: 6306-6316
147 Colunga Biancatelli RML, Berrill M, Catravas JD, Marik PE. Quercetin and vitamin C: An experimental, synergistic therapy for the prevention and treatment of SARS-CoV-2 related disease (COVID-19). Front Immunol 2020; 11: 1-11
148 Mbikay M, Chrétien M. Isoquercetin as an anti-COVID-19 medication: A potential to realize. Front Pharmacol 2022; 13: 1-13
149 Fiorani M, Accorsi A, Cantoni O. Human red blood cells as a natural flavonoid reservoir. Free Radic Res 2003; 37: 1331-1338
150 Guo Y, Mah E, Bruno RS. Quercetin bioavailability is associated with inadequate plasma vitamin C status and greater plasma endotoxin in adults. Nutrition 2014; 30: 1279-1286
151 Martini S, Bonechi C, Rossi C. Interaction of quercetin and its conjugate quercetin 3-O-β-D-glucopyranoside with albumin as determined by NMR relaxation data. J Nat Prod 2008; 71: 175-178
152 Stopa JD, Neuberg D, Puligandla M, Furie B, Flaumenhaft R, Zwicker JI. Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering with platelet factor V activation. JCI Insight 2017; 2: e89373
153 Fiorani M, De Sanctis R, De Bellis R, Dachà M. Intracellular flavonoids as electron donors for extracellular ferricyanide reduction in human erythrocytes. Free Radic Biol Med 2002; 32: 64-72
154 Terao J, Murota K, Kawai Y. Conjugated quercetin glucuronides as bioactive metabolites and precursors of aglycone in vivo . Food Funct 2011; 2: 11-17
155 Gong G, Guan YY, Zhang ZL, Rahman K, Wang SJ, Zhou S, Luan X, Zhang H. Isorhamnetin: a review of pharmacological effects. Biomed Pharmacother 2020; 128: 110301
156 Fan D, Zhou X, Zhao C, Chen H, Zhao Y, Gong X. Anti-inflammatory, antiviral and quantitative study of quercetin-3-O-β-D-glucuronide in Polygonum perfoliatum L. Fitoterapia 2011; 82: 805-810
157 Schwarz S, Sauter D, Wang K, Zhang R, Sun B, Karioti A, Bilia A, Efferth T, Schwarz W. Kaempferol derivatives as antiviral drugs against the 3a channel protein of coronavirus. Planta Med 2014; 80: 177-182
158 Shaldam MA, Yahya G, Mohamed NH, Abdel-Daim MM, Al Naggar Y. In silico screening of potent bioactive compounds from honeybee products against COVID-19 target enzymes. Environ Sci Pollut Res Int 2021; 28: 40507-40514
159 Saeed M, Naveed M, Arif M, Kakar M, Manzoor R, El-Hack M, Alagawany M, Tiwari R, Khandia R, Munjal A, Karthik K, Dhama K, Iqbal H, Dadar M, Sun C. Green tea (Camellia sinensis) andl-theanine: Medicinal values and beneficial applications in humans – a comprehensive review. Biomed Pharmacother 2017; 95: 1260-1275
160 Jena A, Kanungo N, Nayak V, Chainy G, Dandapat J. Catechin and curcumin interact with corona (2019-nCoV/SARS-CoV2) viral S protein and ACE2 of human cell membrane: insights from computational study and implication for intervention. 2020; 11: 2043
161 Henss L, Auste A, Schürmann C, Schmidt C, von Rhein C, Mühlebach MD, Schnierle BS. The green tea catechin epigallocatechin gallate inhibits SARS-CoV- 2 infection. J Gen Virol 2021; 102: 001574
162 Mishra CB, Pandey P, Sharma RD, Malik MZ, Mongre RK, Lynn AM, Prasad R, Jeon R, Prakash A. Identifying the natural polyphenol catechin as a multi-targeted agent against SARS-CoV-2 for the plausible therapy of COVID-19: An integrated computational approach. Brief Bioinform 2021; 22: 1346-1360
163 Mhatre S, Gurav N, Shah M, Patravale V. Entry-inhibitory role of catechins against SARS-CoV-2 and its UK variant. Comput Biol Med 2021; 135: 104560
164 Rabezanahary H, Badr A, Checkmahomed L, Pageau K, Desjardins Y, Baz M. Epigallocatechin gallate and isoquercetin synergize with remdesivir to reduce SARS-COV-2 replication in vitro . Front Virol 2022; 2: 1-9
165 Koch E. Previfenon® as Chemoprophylaxis of COVID-19 in Health Workers – full text view. Accessed 06.11.2023 at: https://clinicaltrials.gov/ct2/show/NCT04446065
166 Song JW, Long JY, Xie L, Zhang LL, Xie QX, Chen HJ, Deng M, Li XF. Applications, phytochemistry, pharmacological effects, pharmacokinetics, toxicity of Scutellaria baicalensis Georgi. and its probably potential therapeutic effects on COVID-19: A review. Chinese Med (United Kingdom) 2020; 15: 1-26
167 Zhao Y, Chen XY, Martin C. Scutellaria baicalensis, the golden herb from the garden of Chinese medicinal plants. Sci Bull 2016; 61: 1391-1398
168 Li Y, Song K, Zhang H, Yuan M, An N, Wei Y, Wang L, Sun Y, Xing Y, Gao Y. Anti-inflammatory and immunomodulatory effects of baicalin in cerebrovascular and neurological disorders. Brain Res Bull 2020; 164: 314-324
169 Zandi K, Musall K, Oo A, Cao D, Liang B, Hassandarvish P, Lan S, Slack RL, Kirby KA, Bassit L, Amblard F, Kim B, AbuBakar S, Sarafianos SG, Schinazi RF. Baicalein and baicalin inhibit SARS-CoV-2 RNA-Dependent-RNA polymerase. Microorganisms 2021; 9: 893
170 Liu H, Ye F, Sun Q, Liang H, Li C, Li S, Lu R, Huang B, Tan W, Lai L. Scutellaria baicalensis extract and baicalein inhibit replication of SARS-CoV-2 and its 3C-like protease in vitro . J Enzyme Inhib Med Chem 2021; 36: 497-503
171 Huang S, Liu Y, Zhang Y, Zhang R, Zhu CJ, Fan L, Pei G, Zhang B, Shi Y. Baicalein inhibits SARS-CoV-2/VSV replication with interfering mitochondrial oxidative phosphorylation in a mPTP dependent manner. Signal Transduct Target Ther 2020; 5: 266
172 Su HX, Yao S, Zhao WF, Li MJ, Liu J, Shang WJ, Xie H, Ke CQ, Hu HC, Gao MN, Yu KQ, Liu H, Shen JS, Tang W, Zhang LK, Xiao GF, Ni L, Wang DW, Zuo JP, Jiang HL, Bai F, Wu Y, Ye Y, Xu YC. Anti-SARS-CoV-2 activities in vitro of Shuanghuanglian preparations and bioactive ingredients. Acta Pharmacol Sin 2020; 41: 1167-1177
173 Jo S, Kim S, Kim D, Kim MS, Shin D. Flavonoids with inhibitory activity against SARS-CoV-2 3CLpro. J Enzyme Inhib Med Chem 2020; 35: 1539-1544
174 Miean KH, Mohamed S. Flavonoid (myricetin, quercetin, kaempferol, luteolin, and apigenin) content of edible tropical plants. J Agric Food Chem 2001; 49: 3106-3112
175 Wong SSY, Yuen KY. The management of coronavirus infections with particular reference to SARS. J Antimicrob Chemother 2008; 62: 437-441
176 Yi L, Li Z, Yuan K, Qu X, Chen J, Wang G, Zhang H, Luo H, Zhu L, Jiang P, Chen L, Shen Y, Luo M, Zuo G, Hu J, Duan D, Nie Y, Shi X, Wang W, Han Y, Li T, Liu Y, Ding M, Deng H, Xu X. Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells. J Virol 2004; 78: 11334-11339
177 Maurya VK, Kumar S, Prasad AK, Bhatt MLB, Saxena SK. Structure-based drug designing for potential antiviral activity of selected natural products from Ayurveda against SARS-CoV-2 spike glycoprotein and its cellular receptor. Virusdisease 2020; 31: 179-193
178 Xie YZ, Peng CW, Su ZQ, Huang HT, Liu XH, Zhan SF, Huang XF. A practical strategy for exploring the pharmacological mechanism of luteolin against COVID-19/asthma comorbidity: Findings of system pharmacology and bioinformatics analysis. Front Immunol 2022; 12: 1-18
179 Di Stadio A, DʼAscanio L, Vaira LA, Cantone E, De Luca P, Cingolani C, Motta G, De Riu G, Vitelli F, Spriano G, De Vincentiis M, Camaioni A, La Mantia I, Ferreli F, Brenner MJ. Ultramicronized palmitoylethanolamide and luteolin supplement combined with olfactory training to treat post-COVID-19 olfactory impairment: A multi-center double-blinded randomized placebo- controlled clinical trial. Curr Neuropharmacol 2022; 20: 2001-2012
180 Yu R, Chen L, Lan R, Shen R, Li P. Computational screening of antagonists against the SARS-CoV-2 (COVID-19) coronavirus by molecular docking. Int J Antimicrob Agents 2020; 56: 106012
181 Shadrack DM, Deogratias G, Kiruri LW, Onoka I, Vianney JM, Swai H, Nyandoro SS. Luteolin: a blocker of SARS-CoV-2 cell entry based on relaxed complex scheme, molecular dynamics simulation, and metadynamics. J Mol Model 2021; 27: 221
182 Españo E, Kim J, Lee K, Kim JK. Phytochemicals for the treatment of COVID-19. J Microbiol 2021; 59: 959-977
183 Aniszewski T. Alkaloids – secrets of life. Amsterdam: Elsevier Science; 2007: 1-59
184 Schmeller T, Latz-Brüning B, Wink M. Biochemical activities of berberine, palmatine and sanguinarine mediating chemical defence against microorganisms and herbivores. Phytochemistry 1997; 44: 257-266
185 Wink M, Schimmer O. Modes of Action of Defensive Secondary Metabolites. In: Roberts JA. ed. Annual Plant Reviews Online. Hoboken: John Wiley & Sons; 2018: 21-161
186 Wink M, Schmeller T, Latz-Brüning B. Modes of action of allelochemical alkaloids: interaction with neuroreceptors, DNA, and other molecular targets. J Chem Ecol 1998; 24: 1881-1937.:
187 Wink M. Chapter 1 molecular modes of action of cytotoxic alkaloids: From DNA intercalation, spindle poisoning, topoisomerase inhibition to apoptosis and multiple drug resistance. Alkaloids Chem Biol 2007; 64: 1-47
188 Li S, Chen C, Zhang H, Guo H, Wang H, Wang L, Zhang X, Hua S, Yu J, Xiao P. Identification of natural compounds with antiviral activities against SARS-associated coronavirus. Antiviral Res 2005; 67: 18-23
189 Alfaro M, Alfaro I, Angel C. Identification of potential inhibitors of SARS-CoV-2 papain-like protease from tropane alkaloids from Schizanthus porrigens: a molecular docking study. Chem Phys Lett 2020; 761: 138068
190 Borquaye L, Gasu E, Boadu G, Kyei L, Amarh M, Mensah C, Nartey D, Commodore M, Adomako A, Acheampong P, Mensah J, Mormor D. Alkaloids from Cryptolepis sanguinolenta as potential inhibitors of SARS-CoV-2 viral proteins: An in silico study. Biomed Res Int 2020; 2020: 1-14
191 Kar P, Kumar V, Balachandar V, Sen A, Jaishee N, Anandraj A, Malhotra H, Bhattacharyya S, Mukhopadhyay S, Kinoshita M, Govindasami V, Roy A, Naidoo D, Subramaniam MD. Anisotine and amarogentin as promising inhibitory candidates against SARS-CoV-2 proteins: A computational investigation. J Biomol Struct Dyn 2020; 40: 4532-4542
192 Garg S, Roy A. In silico analysis of selected alkaloids against main protease (Mpro) of SARS-CoV-2. Chem Biol Interact 2020; 332: 109309
193 Karatza E, Ismailos G, Karalis V. Colchicine for the treatment of COVID-19 patients: Efficacy, safety, and model informed dosage regimens. Xenobiotica 2021; 51: 643-656
194 U. S. Food and Drug Administration. Colchicine (marketed as Colcrys) Information. Accessed March 9, 2023 at: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/colchicine-marketed-colcrys-information
195 Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006; 440: 237-241
196 Marques-da-Silva C, Chaves MM, Castro NG, Coutinho-Silva R, Guimaraes MZP. Colchicine inhibits cationic dye uptake induced by ATP in P2X2 and P2X7 receptor-expressing cells: Implications for its therapeutic action. Br J Pharmacol 2011; 163: 912-926
197 Abbate A, Toldo S, Marchetti C, Kron J, Van Tassell BW, Dinarello CA. Interleukin-1 and the inflammasome as therapeutic targets in cardiovascular disease. Circ Res 2020; 126: 1260-1280
198 Drosos AA, Pelechas E, Drossou V, Voulgari PV. Colchicine against SARS-CoV-2 infection: What is the evidence?. Rheumatol Ther 2022; 9: 379-389
199 Deftereos SG, Giannopoulos G, Vrachatis DA, Siasos GD, Giotaki SG, Gargalianos P, Metallidis S, Sianos G, Baltagiannis S, Panagopoulos P, Dolianitis K, Randou E, Syrigos K, Kotanidou A, Koulouris NG, Milionis H, Sipsas N, Gogos C, Tsoukalas G, Olympios CD, Tsagalou E, Migdalis I, Gerakari S, Angelidis C, Alexopoulos D, Davlouros P, Hahalis G, Kanonidis I, Katritsis D, Kolettis T, Manolis AS, Michalis L, Naka KK, Pyrgakis VN, Toutouzas KP, Triposkiadis F, Tsioufis K, Vavouranakis E, Martinèz-Dolz L, Reimers B, Stefanini GG, Cleman M, Goudevenos J, Tsiodras S, Tousoulis D, Iliodromitis E, Mehran R, Dangas G, Stefanadis C. GRECCO-19 investigators. Effect of colchicine vs. standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: The GRECCO-19 randomized clinical trial. JAMA Netw Open 2020; 3: e2013136
200 Brunetti L, Diawara O, Tsai A, Firestein BL, Nahass RG, Poiani G, Schlesinger N. Colchicine to weather the cytokine storm in hospitalized patients with COVID-19. J Clin Med 2020; 9: 2961
201 Della-Torre E, Della-Torre F, Kusanovic M, Scotti R, Ramirez GA, Dagna L, Tresoldi M. Treating COVID-19 with colchicine in community healthcare setting. Clin Immunol 2020; 217: 108490
202 Lopes MI, Bonjorno LP, Giannini MC, Amaral NB, Menezes PI, Dib SM, Gigante SL, Benatti MN, Rezek UC, Emrich-Filho LL, Sousa BAA, Almeida SCL, Luppino Assad R, Veras FP, Schneider A, Rodrigues TS, Leiria LOS, Cunha LD, Alves-Filho JC, Cunha TM, Arruda E, Miranda CH, Pazin-Filho A, Auxiliadora-Martins M, Borges MC, Fonseca BAL, Bollela VR, Del-Ben CM, Cunha FQ, Zamboni DS, Santana RC, Vilar FC, Louzada-Junior P, Oliveira RDR. Beneficial effects of colchicine for moderate to severe COVID-19: A randomised, double-blinded, placebo-controlled clinical trial. RMD Open 2021; 7: e001455
203 Manenti L, Maggiore U, Fiaccadori E, Meschi T, Antoni AD, Nouvenne A, Ticinesi A, Cerundolo N, Prati B, Delsante M, Gandoflini I, Donghi L, Gentile M, Farina MT, Oliva V, Zambrano C, Regolisti G, Palmisano A, Caminiti C, Cocchi E, Ferrari C, Riella LV, Cravedi P, Peruzzi L. Reduced mortality in COVID-19 patients treated with colchicine: Results from a retrospective, observational study. PLoS One 2021; 16: e0248276
204 Sandhu T, Tieng A, Chilimuri S, Franchin G. A case control study to evaluate the impact of colchicine on patients admitted to the hospital with moderate to severe COVID-19 infection. Can J Infect Dis Med Microbiol 2020; 2020: 8865954
205 Scarsi M, Piantoni S, Colombo E, Airó P, Richini D, Miclini M, Bertasi V, Bianchi M, Bottone D, Civelli P, Cotelli MS, Damiolini E, Galbassini G, Gatta D, Ghirardelli ML, Magri R, Malamani P, Mendeni M, Molinari S, Morotti A, Salada L, Turla M, Vender A, Tincani A, Brucato A, Franceschini F, Furloni R, Andreoli L. Association between treatment with colchicine and improved survival in a single-centre cohort of adult hospitalised patients with COVID-19 pneumonia and acute respiratory distress syndrome. Ann Rheum Dis 2020; 79: 1286-1289
206 Tardif JC, Bouabdallaoui N, LʼAllier PL, Gaudet D, Shah B, Pillinger MH, Lopez-Sendon J, da Luz P, Verret L, Audet S, Dupuis J, Denault A, Pelletier M, Tessier PA, Samson S, Fortin D, Tardif JD, Busseuil D, Goulet E, Lacoste C, Dubois A, Joshi AY, Waters DD, Hsue P, Lepor NE, Lesage F, Sainturet N, Roy-Clavel E, Bassevitch Z, Orfanos A, Stamatescu G, Grégoire JC, Busque L, Lavallée C, Hétu PO, Paquette JS, Deftereos SG, Levesque S, Cossette M, Nozza A, Chabot-Blanchet M, Dubé MP, Guertin MC, Boivin G. COLCORONA Investigators. Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial. Lancet Respir Med 2021; 9: 924-932
207 Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): A randomised, controlled, open-label, platform trial. Lancet Respir Med 2021; 9: 1419-1426
208 Kamran S, Sinniah A, Abdulghani MAM, Alshawsh MA. Therapeutic potential of certain terpenoids as anticancer agents: a scoping review. Cancers (Basel) 2022; 14: 1100
209 Kulkarni S, Nagarajan SK, Ramesh V, Palaniyandi V, Sellamuthu P, Madhavan T. Computational evaluation of major components from plant essential oils as potent inhibitors of SARS-CoV-2 spike protein. J Mol Struct 2020; 1221: 128823
210 Carino A, Moraca F, Fiorillo B, Marchianò S, Sepe V, Biagioli M, Finamore C, Bozza S, Francisci D, Distrutti E, Catalanotti B, Zampella A, Fiorucci S. Hijacking SARS-CoV-2/ACE2 receptor interaction by natural and semi-synthetic steroidal agents acting on functional pockets on the receptor binding domain. Front Chem 2020; 8: 1-15
211 Singh S, Florez H. Bioinformatic study to discover natural molecules with activity against COVID-19. F1000Res 2020; 9: 1203
212 Malekmohammad K, Rafieian-Kopaei M. Mechanistic aspects of medicinal plants and secondary metabolites against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Curr Pharm Des 2021; 27: 3996-4007
213 Chikhale R, Gurav S, Patil DR, Sinha DS, Prasad DS, Shakya A, Shrivastava S, Gurav N, Prasad R. Sars-CoV-2 host entry and replication inhibitors from Indian ginseng: An in-silico approach. J Biomol Struct Dyn 2020; 39: 4510-4521
214 Siddiqui S, Upadhyay S, Ahmad R, Gupta A, Srivastava A, Trivedi A, Husain I, Ahmad B, Ahamed M, Khan MA. Virtual screening of phytoconstituents from miracle herb nigella sativa targeting nucleocapsid protein and papain-like protease of SARS-CoV-2 for COVID-19 treatment. J Biomol Struct Dyn 2022; 40: 3928-3948
215 Diniz LRL, Perez-Castillo Y, Elshabrawy HA, Filho CSMB, de Sousa DP. Bioactive terpenes and their derivatives as potential SARS-CoV-2 proteases inhibitors from molecular modeling studies. Biomolecules 2021; 11: 74
216 Giofrè SV, Napoli E, Iraci N, Speciale A, Cimino F, Muscarà C, Molonia MS, Ruberto G, Saija A. Interaction of selected terpenoids with two SARS-CoV-2 key therapeutic targets: An in silico study through molecular docking and dynamics simulations. Comput Biol Med 2021; 134: 104538
217 Park JY, Kim JH, Kim Y, Jeong H, Kim D, Park K, Kwon HJ, Park SC, Lee W, Ryu Y. Tanshinones as selective and slow-binding inhibitors for SARS-CoV cysteine proteases. Bioorg Med Chem 2012; 20: 5928-5935
218 Falade VA, Adelusi TI, Adedotun IO, Abdul-Hammed M, Lawal TA, Agboluaje SA. In silico investigation of saponins and tannins as potential inhibitors of SARS-CoV-2 main protease (Mpro). Silico Pharmacol 2021; 9: 1-15
219 Sun H, Xie Y, Ye YP. Advances in saponin-based adjuvants. Vaccine 2009; 27: 1787-1796
220 Skene CD, Sutton P. Saponin-adjuvanted particulate vaccines for clinical use. Methods 2006; 40: 53-59
221 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
222 He MF, Liang JH, Shen YN, Zhang JW, Liu Y, Yang KY, Liu LC, Wang J, Xie Q, Hu C, Song X, Wang Y. Glycyrrhizin inhibits SARS-CoV-2 entry into cells by targeting ACE2. Life 2022; 12: 1706
223 Behl T, Rocchetti G, Chadha S, Zengin G, Bungau S, Kumar A, Mehta V, Uddin MS, Khullar G, Setia D, Arora S, Sinan KI, Ak G, Putnik P, Gallo M, Montesano D. Phytochemicals from plant foods as potential source of antiviral agents: An overview. Pharmaceuticals 2021; 14: 1-46
224 Khalifa I, Zhu W, Mohammed HHH, Dutta K, Li C. Tannins inhibit SARS-CoV-2 through binding with catalytic dyad residues of 3CLpro: An in silico approach with 19 structural different hydrolysable tannins. J Food Biochem 2020; 44: 1-19
225 Wang SC, Chen Y, Wang YC, Wang WJ, Yang CS, Tsai CL, Hou MH, Chen HF, Shen YC, Hung MC. Tannic acid suppresses SARS-CoV-2 as a dual inhibitor of the viral main protease and the cellular TMPRSS2 protease. Am J Cancer Res 2020; 10: 4538-4546
226 Zhang YN, Zhang QY, Li XD, Xiong J, Xiao SQ, Wang Z, Zhang ZR, Deng CL, Yang XL, Wei HP, Yuan ZM, Ye HQ, Zhang B. Gemcitabine, lycorine and oxysophoridine inhibit novel coronavirus (SARS-CoV-2) in cell culture. Emerg Microbes Infect 2020; 9: 1170-1173
227 He CL, Huang LY, Wang K, Gu CJ, Hu J, Zhang GJ, Xu W, Xie YH, Tang N, Huang AL. Identification of bis-benzylisoquinoline alkaloids as SARS-CoV-2 entry inhibitors from a library of natural products. Signal Transduct Target Ther 2021; 6: 2020-2022
228 Jan JT, Cheng TJR, Juang YP, Ma HH, Wu YT, Yang WB, Cheng CW, Chen X, Chou TH, Shie JJ, Cheng WC, Chein RJ, Mao SS, Liang PH, Ma C, Hung SC, Wong CH. Identification of existing pharmaceuticals and herbal medicines as inhibitors of SARS-CoV-2 infection. Proc Natl Acad Sci U S A 2021; 118: 1-8
229 Ohashi H, Watashi K, Saso W, Shionoya K, Iwanami S, Hirokawa T, Shirai T, Kanaya S, Ito Y, Kim KS, Nomura T, Suzuki T, Nishioka K, Ando S, Ejima K, Koizumi Y, Tanaka T, Aoki S, Kuramochi K, Suzuki T, Hashiguchi T, Maenaka K, Matano T, Muramatsu M, Saijo M, Aihara K, Iwami S, Takeda M, McKeating JA, Wakita T. Potential anti-COVID-19 agents, cepharanthine and nelfinavir, and their usage for combination treatment. iScience 2021; 24: 102367
230 Varghese FS, van Woudenbergh E, Overheul GJ, Eleveld MJ, Kurver L, van Heerbeek N, van Laarhoven A, Miesen P, den Hartog G, de Jonge MI, van Rij RP. Berberine and obatoclax inhibit SARS-Cov-2 replication in primary human nasal epithelial cells in vitro . Viruses 2021; 13: 282
231 Pizzorno A, Padey B, Dubois J, Julien T, Traversier A, Dulière V, Brun P, Lina B, Rosa-Calatrava M, Terrier O. In vitro evaluation of antiviral activity of single and combined repurposable drugs against SARS-CoV-2. Antiviral Res 2020; 181: 104878
232 Xia B, Shen X, He Y, Pan X, Liu FL, Wang Y, Yang F, Fang S, Wu Y, Duan Z, Zuo X, Xie Z, Jiang X, Xu L, Chi H, Li S, Meng Q, Zhou H, Zhou Y, Cheng X, Xin X, Jin L, Zhang HL, Yu DD, Li MH, Feng XL, Chen J, Jiang H, Xiao G, Zheng YT, Zhang LK, Shen J, Li J, Gao Z. SARS-CoV-2 envelope protein causes acute respiratory distress syndrome (ARDS)-like pathological damages and constitutes an antiviral target. Cell Res 2021; 31: 847-860
233 Huang L, Yuen TTT, Ye Z, Liu S, Zhang G, Chu H, Yue J. Berbamine inhibits SARS-CoV-2 infection by compromising TRPMLs-mediated endolysosomal trafficking of ACE2. Signal Transduct Target Ther 2021; 6: 168
234 Gyebi GA, Ogunro OB, Adegunloye AP, Ogunyemi OM, Afolabi SO. Potential inhibitors of coronavirus 3-chymotrypsin-like protease (3CLpro): An in silico screening of alkaloids and terpenoids from African medicinal plants. J Biomol Struct Dyn 2021; 39: 3396-3408
235 Yang Y, Yang P, Huang C, Wu Y, Zhou Z, Wang X, Wang S. Inhibitory effect on SARS-CoV-2 infection of neferine by blocking Ca(2+) -dependent membrane fusion. J Med Virol 2021; 93: 5825-5832
236 Choy KT, Wong AYL, Kaewpreedee P, Sia SF, Chen D, Hui KPY, Chu DKW, Chan MCW, Cheung PPH, Huang X, Peiris M, Yen HL. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro . Antiviral Res 2020; 178: 104786
237 Ku KB, Shin HJ, Kim HS, Kim BT, Kim SJ, Kim C. Repurposing screens of FDA-approved drugs identify 29 inhibitors of SARS-CoV-2. J Microbiol Biotechnol 2020; 30: 1843-1853
238 Tsai YC, Lee CL, Yen HR, Chang YS, Lin YP, Huang SH, Lin CW. Antiviral action of tryptanthrin isolated from Strobilanthes cusia leaf against human coronavirus nl63. Biomolecules 2020; 10: 366
239 Fan S, Zhen Q, Chen C, Wang W, Wu Q, Ma H, Zhang C, Zhang L, Lu B, Ge H, Yong L, Li B, Yu Y, Chen W, Mao Y, Qu G, Su L, Wang A, Ding Z, Li H, Zhang J, Wang Y, Gao Y, Xu X, Zhu Z, Chen J, Zhang L, Liang H, Wu S, Huang M, Xia Q, Li P, Sun Y, Liang C, Wei W, Liu Q, Sun L. Clinical efficacy of low-dose emetine for patients with COVID-19: A real-world study. J bio-X Res 2021; 4: 53-59
240 Kumar R, Afsar M, Khandelwal N, Chander Y, Riyesh T, Kumar R, Gulati BR, Pal Y, Barua S, Tripathi BN, Hussain T, Kumar N. Emetine suppresses SARS-CoV-2 replication by inhibiting interaction of viral mRNA with eIF4E. Antiviral Res 2021; 189: 105056
241 Wang A, Sun Y, Liu Q, Wu H, Liu J, He J, Yu J, Chen QQ, Ge Y, Zhang Z, Hu C, Chen C, Qi Z, Zou F, Liu F, Hu J, Zhao M, Huang T, Wang B, Wang L, Wang W, Wang W, Ren T, Liu J, Sun Y, Fan S, Wu Q, Liang C, Sun L, Su B, Wei W, Liu Q. Low dose of emetine as potential anti-SARS-CoV-2 virus therapy: preclinical in vitro inhibition and in vivo pharmacokinetic evidences. Mol Biomed 2020; 1: 14
242 Shree P, Mishra P, Selvaraj C, Singh SK, Chaube R, Garg N, Tripathi YB. Targeting COVID-19 (SARS-CoV-2) main protease through active phytochemicals of Ayurvedic medicinal plants – Withania somnifera (ashwagandha), Tinospora cordifolia (giloy) and Ocimum sanctum (tulsi) – a molecular docking study. J Biomol Struct Dyn 2022; 40: 190-203
243 Mohammadi S, Heidarizadeh M, Entesari M, Esmailpour A, Esmailpour M, Moradi R, Sakhaee N, Doustkhah E. In silico investigation on the inhibiting role of nicotine/caffeine by blocking the S protein of SARS-CoV-2 versus ACE2 receptor. Microorganisms 2020; 8: 1600
244 Elzupir AO. Caffeine and caffeine-containing pharmaceuticals as promising inhibitors for 3-chymotrypsin-like protease of SARS-CoV-2. J Biomol Struct Dyn 2022; 40: 2113-2120
245 Yang CW, Lee YZ, Hsu HY, Shih C, Chao YS, Chang HY, Lee SJ. Targeting coronaviral replication and cellular JAK2 mediated dominant NF-κB activation for comprehensive and ultimate inhibition of coronaviral activity. Sci Rep 2017; 7: 4105
246 Yang CW, Lee YZ, Kang IJ, Barnard DL, Jan JT, Lin D, Huang CW, Yeh TK, Chao YS, Lee SJ. Identification of phenanthroindolizines and phenanthroquinolizidines as novel potent anti-coronaviral agents for porcine enteropathogenic coronavirus transmissible gastroenteritis virus and human severe acute respiratory syndrome coronavirus. Antiviral Res 2010; 88: 160-168
247 Lin CW, Tsai FJ, Tsai CH, Lai CC, Wan L, Ho TY, Hsieh CC, Chao PDL. Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds. Antiviral Res 2005; 68: 36-42
248 Große M, Ruetalo N, Layer M, Hu D, Businger R, Rheber S, Setz C, Rauch P, Auth J, Fröba M, Brysch E, Schindler M, Schubert U. Quinine inhibits infection of human cell lines with SARS-CoV-2. Viruses 2021; 13: 647
249 Clarke EC, Nofchissey RA, Ye C, Bradfute SB. The iminosugars celgosivir, castanospermine and UV-4 inhibit SARS-CoV-2 replication. Glycobiology 2021; 31: 378-384
250 Raj V, Park JG, Cho KH, Choi P, Kim T, Ham J, Lee J. Assessment of antiviral potencies of cannabinoids against SARS-CoV-2 using computational and in vitro approaches. Int J Biol Macromol 2021; 168: 474-485
251 Nguyen LC, Yang D, Nicolaescu V, Best TJ, Gula H, Saxena D, Gabbard JD, Chen SN, Ohtsuki T, Friesen JB, Drayman N, Mohamed A, Dann C, Silva D, Robinson-Mailman L, Valdespino A, Stock L, Suárez E, Jones KA, Azizi SA, Demarco JK, Severson WE, Anderson CD, Millis JM, Dickinson BC, Tay S, Oakes SA, Pauli GF. Palmer KE; National COVID Cohort Collaborative Consortium, Meltzer DO, Randall G, Rosner MR. Cannabidiol inhibits SARS-CoV-2 replication through induction of the host ER stress and innate immune responses. Sci Adv 2022; 8: eabi6110
252 van Breemen RB, Muchiri RN, Bates TA, Weinstein JB, Leier HC, Farley S, Tafesse FG. Cannabinoids block cellular entry of SARS-CoV-2 and the emerging variants. J Nat Prod 2022; 85: 176-184
253 Yang QY, Tian XY, Fang WS. Bioactive coumarins from Boenninghausenia sessilicarpa . J Asian Nat Prod Res 2007; 9: 59-65
254 Cho JK, Curtis-Long MJ, Lee KH, Kim DW, Ryu HW, Yuk HJ, Park KH. Geranylated flavonoids displaying SARS-CoV papain-like protease inhibition from the fruits of Paulownia tomentosa . Bioorganic Med Chem 2013; 21: 3051-3057
255 Kim DW, Seo KH, Curtis-Long MJ, Oh KY, Oh JW, Cho JK, Lee KH, Park KH. Phenolic phytochemical displaying SARS-CoV papain-like protease inhibition from the seeds of Psoralea corylifolia . J Enzyme Inhib Med Chem 2014; 29: 59-63
256 Park JY, Jeong HJ, Kim JH, Kim YM, Park SJ, Kim D, Park KH, Lee WS, Ryu YB. Diarylheptanoids from Alnus japonica inhibit papain-like protease of severe acute respiratory syndrome coronavirus. Biol Pharm Bull 2012; 35: 2036-2042
257 Valizadeh H, Abdolmohammadi-Vahid S, Danshina S, Ziya Gencer M, Ammari A, Sadeghi A, Roshangar L, Aslani S, Esmaeilzadeh A, Ghaebi M, Valizadeh S, Ahmadi M. Nano-curcumin therapy, a promising method in modulating inflammatory cytokines in COVID-19 patients. Int Immunopharmacol 2020; 89: 107088
258 Pawar KS, Mastud RN, Pawar SK, Pawar SS, Bhoite RR, Bhoite RR, Kulkarni MV, Deshpande AR. Oral curcumin with piperine as adjuvant therapy for the treatment of COVID-19: A randomized clinical trial. Front Pharmacol 2021; 12: 669362
259 Goc A, Sumera W, Rath M, Niedzwiecki A. Phenolic compounds disrupt spike-mediated receptor-binding and entry of SARS-CoV-2 pseudo-virions. PLoS One 2021; 16: e0253489
260 Bormann M, Alt M, Schipper L, van de Sand L, Le-Trilling VTK, Rink L, Heinen N, Madel RJ, Otte M, Wuensch K, Heilingloh CS, Mueller T, Dittmer U, Elsner C, Pfaender S, Trilling M, Witzke O, Krawczyk A. Turmeric root and its bioactive ingredient curcumin effectively neutralize SARS-CoV-2 in vitro . Viruses 2021; 13: 1914
261 Du R, Cooper L, Chen Z, Lee H, Rong L, Cui Q. Discovery of chebulagic acid and punicalagin as novel allosteric inhibitors of SARS-CoV-2 3CLpro. Antiviral Res 2021; 190: 105075
262 Tito A, Colantuono A, Pirone L, Pedone E, Intartaglia D, Giamundo G, Conte I, Vitaglione P, Apone F. Pomegranate peel extract as an inhibitor of SARS-CoV-2 spike binding to human ACE2 receptor (in vitro): A promising source of novel antiviral drugs. Front Chem 2021; 9: 638187
263 Nishimura H, Okamoto M, Dapat I, Katsumi M, Oshitani H. Inactivation of SARS-CoV-2 by catechins from green tea. Jpn J Infect Dis 2021; 74: 421-423
264 Hong S, Seo SH, Woo SJ, Kwon Y, Song M, Ha NC. Epigallocatechin gallate inhibits the uridylate-specific endoribonuclease Nsp15 and efficiently neutralizes the SARS-CoV-2 strain. J Agric Food Chem 2021; 69: 5948-5954
265 Jang M, Park YI, Cha YE, Park R, Namkoong S, Lee JI, Park J. Tea polyphenols EGCG and theaflavin inhibit the activity of SARS-CoV-2 3CL-protease in vitro . Evid Based Complement Alternat Med 2020; 2020: 1-7
266 Ohgitani E, Shin-Ya M, Ichitani M, Kobayashi M, Takihara T, Kawamoto M, Kinugasa H, Mazda O. Significant inactivation of sars-cov-2 in vitro by a green tea catechin, a catechin-derivative, and black tea galloylated theaflavins. Molecules 2021; 26: 3572
267 Park JY, Ko JA, Kim DW, Kim YM, Kwon HJ, Jeong HJ, Kim CY, Park KH, Lee WS, Ryu YB. Chalcones isolated from Angelica keiskei inhibit cysteine proteases of SARS-CoV. J Enzyme Inhib Med Chem 2016; 31: 23-30
268 Kanjanasirirat P, Suksatu A, Manopwisedjaroen S, Munyoo B, Tuchinda P, Jearawuttanakul K, Seemakhan S, Charoensutthivarakul S, Wongtrakoongate P, Rangkasenee N, Pitiporn S, Waranuch N, Chabang N, Khemawoot P, Sa-Ngiamsuntorn K, Pewkliang Y, Thongsri P, Chutipongtanate S, Hongeng S, Borwornpinyo S, Thitithanyanont A. High-content screening of Thai medicinal plants reveals Boesenbergia rotunda extract and its component panduratin A as anti-SARS-CoV-2 agents. Sci Rep 2020; 10: 1-12
269 Abdallah HM, El-Halawany AM, Sirwi A, El-Araby AM, Mohamed GA, Ibrahim SRM, Koshak AE, Asfour HZ, Awan ZA, Elfaky MA. Repurposing of some natural product isolates as SARS-COV-2 main protease inhibitors via in vitro cell free and cell-based antiviral assessments and molecular modeling approaches. Pharmaceuticals (Basel) 2021; 14: 213
270 Clementi N, Scagnolari C, DʼAmore A, Palombi F, Criscuolo E, Frasca F, Pierangeli A, Mancini N, Antonelli G, Clementi M, Carpaneto A, Filippini A. Naringenin is a powerful inhibitor of SARS-CoV-2 infection in vitro . Pharmacol Res 2021; 163: 12-15
271 Jo S, Kim S, Shin DH, Kim MS. Inhibition of SARS-CoV 3CL protease by flavonoids. J Enzyme Inhib Med Chem 2020; 35: 145-151
272 Pitsillou E, Liang J, Ververis K, Lim KW, Hung A, Karagiannis TC. Identification of small molecule inhibitors of the deubiquitinating activity of the SARS-CoV-2 papain-like protease: in silico molecular docking studies and in vitro enzymatic activity assay. Front Chem 2020; 8: 623971
273 Abian O, Ortega-Alarcon D, Jimenez-Alesanco A, Ceballos-Laita L, Vega S, Reyburn HT, Rizzuti B, Velazquez-Campoy A. Structural stability of SARS-CoV-2 3CLpro and identification of quercetin as an inhibitor by experimental screening. Int J Biol Macromol 2020; 164: 1693-1703
274 Pandey P, Rane JS, Chatterjee A, Kumar A, Khan R, Prakash A, Ray S. Targeting SARS-CoV-2 spike protein of COVID-19 with naturally occurring phytochemicals: an in silico study for drug development. J Biomol Struct Dyn 2020; 0: 1-11
275 Ryu YB, Jeong HJ, Kim JH, Kim YM, Park JY, Kim D, Nguyen TTH, Park SJ, Chang JS, Park KH, Rho MC, Lee WS. Biflavonoids from Torreya nucifera displaying SARS-CoV 3CL(pro) inhibition. Bioorg Med Chem 2010; 18: 7940-7947
276 Khan A, Wang H, Wang Y, Qiu J, Wei X, Peng S, Saleem S, Khan M, Ali S, Wei DQ. In silico and in vitro evaluation of kaempferol as a potential inhibitor of the SARS-CoV-2 main protease (3CLpro). Phyther Res 2020; 35: 2841-2845
277 Yu MS, Lee J, Lee JM, Kim Y, Chin YW, Jee JG, Keum YS, Jeong YJ. Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13. Bioorg Med Chem Lett 2012; 22: 4049-4054
278 Su H, Yao S, Zhao W, Zhang Y, Liu J, Shao Q, Wang Q, Li M, Xie H, Shang W, Ke C, Feng L, Jiang X, Shen J, Xiao G, Jiang H, Zhang L, Ye Y, Xu Y. Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease. Nat Commun 2021; 12: 1-12
279 Zhan Y, Ta W, Tang W, Hua R, Wang J, Wang C, Lu W. Potential antiviral activity of isorhamnetin against SARS-CoV-2 spike pseudotyped virus in vitro . Drug Dev Res 2021; 82: 1124-1130
280 Ogunyemi OM, Gyebi GA, Elfiky AA, Afolabi SO, Ogunro OB, Adegunloye AP, Ibrahim IM. Alkaloids and flavonoids from African phytochemicals as potential inhibitors of SARS-Cov-2 RNA-dependent RNA polymerase: an in silico perspective. Antivir Chem Chemother 2020; 28: 2040206620984076
281 Armstrong LA, Lange SM, Cesare VD, Matthews SP, Nirujogi RS, Cole I, Hope A, Cunningham F, Toth R, Mukherjee R, Bojkova D, Gruber F, Gray D, Wyatt PG, Cinatl J, Dikic I, Davies P, Kulathu Y. Biochemical characterization of protease activity of Nsp3 from SARS-CoV-2 and its inhibition by nanobodies. PLoS One 2021; 16: e0253364
282 Wen CC, Kuo YH, Jan JT, Liang PH, Wang SY, Liu HG, Lee CK, Chang ST, Kuo CJ, Lee SS, Hou CC, Hsiao PW, Chien SC, Shyur LF, Yang NS. Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus. J Med Chem 2007; 50: 4087-4095
283 Ma Q, Li R, Pan W, Huang W, Liu B, Xie Y, Wang Z, Li C, Jiang H, Huang J, Shi Y, Dai J, Zheng K, Li X, Hui M, Fu L, Yang Z. Phillyrin (KD-1) exerts anti-viral and anti-inflammatory activities against novel coronavirus (SARS-CoV-2) and human coronavirus 229E (HCoV-229E) by suppressing the nuclear factor kappa B (NF-κB) signaling pathway. Phytomedicine 2020; 78: 153296
284 Stefanik M, Strakova P, Haviernik J, Miller AD, Ruzek D, Eyer L. Antiviral activity of vacuolar ATPase blocker diphyllin against SARS-COV-2. Microorganisms 2021; 9: 1-10
285 Chen Z, Cui Q, Cooper L, Zhang P, Lee H, Chen Z, Wang Y, Liu X, Rong L, Du R. Ginkgolic acid and anacardic acid are specific covalent inhibitors of SARS-CoV-2 cysteine proteases. Cell Biosci 2021; 11: 1-8
286 El Gizawy HA, Boshra SA, Mostafa A, Mahmoud SH, Ismail MI, Alsfouk AA, Taher AT, Al-Karmalawy AA. Pimenta dioica (L.) merr. bioactive constituents exert anti-sars-cov-2 and anti-inflammatory activities: molecular docking and dynamics, in vitro, and in vivo studies. Molecules 2021; 26: 5844
287 David AB, Diamant E, Dor E, Barnea A, Natan N, Levin L, Chapman S, Mimran LC, Epstein E, Zichel R, Torgeman A. Identification of SARS-CoV-2 receptor binding inhibitors by in vitro screening of drug libraries. Molecules 2021; 26: 1-12
288 Rathinavel T, Palanisamy M, Palanisamy S, Subramanian A, Thangaswamy S. Phytochemical 6-gingerol – A promising drug of choice for COVID-19. Int J Adv Sci Eng 2020; 06: 1482-1489
289 Gangadevi S, Badavath VN, Thakur A, Yin N, De Jonghe S, Acevedo O, Jochmans D, Leyssen P, Wang K, Neyts J, Yujie T, Blum G. Kobophenol A inhibits binding of host ACE2 receptor with spike RBD domain of SARS-CoV-2, a lead compound for blocking COVID-19. J Phys Chem Lett 2021; 12: 1793-1802
290 Pasquereau S, Nehme Z, Haidar Ahmad S, Daouad F, Van Assche J, Wallet C, Schwartz C, Rohr O, Morot-Bizot S, Herbein G. Resveratrol inhibits HCoV-229E and SARS-CoV-2 coronavirus replication in vitro . Viruses 2021; 13: 354
291 Yang M, Wei J, Huang T, Lei L, Shen C, Lai J, Yang M, Liu L, Yang Y, Liu G, Liu Y. Resveratrol inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in cultured Vero cells. Phyther Res 2021; 35: 1127-1129
292 Ter Ellen BM, Kumar ND, Bouma EM, Troost B, van de Pol DPI, van der Ende-Metselaar HH, Apperloo L, van Gosliga D, van den Berge M, Nawijn MC, van der Voort PHJ, Moser J, Rodenhuis-Zybert IA, Smit JM. Resveratrol and pterostilbene inhibit SARS-CoV-2 replication in air–liquid interface cultured human primary bronchial epithelial cells. Viruses 2021; 13: 1335
293 Pitsillou E, Liang J, Karagiannis C, Ververis K, Darmawan KK, Ng K, Hung A, Karagiannis TC. Interaction of small molecules with the SARS-CoV-2 main protease in silico and in vitro validation of potential lead compounds using an enzyme-linked immunosorbent assay. Comput Biol Chem 2020; 89: 107408
294 Cao R, Hu H, Li Y, Wang X, Xu M, Liu J, Zhang H, Yan Y, Zhao L, Li W, Zhang T, Xiao D, Guo X, Li Y, Yang J, Hu Z, Wang M, Zhong W. Anti-SARS-CoV-2 potential of artemisinins in vitro . ACS Infect Dis 2020; 6: 2524-2531
295 Nie C, Trimpert J, Moon S, Haag R, Gilmore K, Kaufer BB, Seeberger PH. In vitro efficacy of Artemisia extracts against SARS-CoV-2. Virol J 2021; 18: 1-7
296 Nair MS, Huang Y, Fidock DA, Polyak SJ, Wagoner J, Towler MJ, Weathers PJ. Artemisia annua L. extracts inhibit the in vitro replication of SARS-CoV-2 and two of its variants. J Ethnopharmacol 2021; 274: 114016
297 Zhou Y, Gilmore K, Ramirez S, Settels E, Gammeltoft KA, Pham LV, Fahnøe U, Feng S, Offersgaard A, Trimpert J, Bukh J, Osterrieder K, Gottwein JM, Seeberger PH. In vitro efficacy of artemisinin-based treatments against SARS-CoV-2. Sci Rep 2021; 11: 14571
298 Li G, Yuan M, Li H, Deng C, Wang Q, Tang Y, Zhang H, Yu W, Xu Q, Zou Y, Yuan Y, Guo J, Jin C, Guan X, Xie F, Song J. Safety and efficacy of artemisinin-piperaquine for treatment of COVID-19: An open-label, non-randomised and controlled trial. Int J Antimicrob Agents 2021; 57: 106216
299 Sehailia M, Chemat S. Antimalarial-agent artemisinin and derivatives portray more potent binding to Lys353 and Lys31-binding hotspots of SARS-CoV-2 spike protein than hydroxychloroquine: Potential repurposing of artenimol for COVID-19. J Biomol Struct Dyn 2021; 39: 6184-6194
300 Lim CT, Tan KW, Wu M, Ulferts R, Armstrong LA, Ozono E, Drury LS, Milligan JC, Zeisner TU, Zeng J, Weissmann F, Canal B, Bineva-Todd G, Howell M, OʼReilly N, Beale R, Kulathu Y, Labib K, Diffley JFX. Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp3 papain-like protease. Biochem J 2021; 478: 2517-2531
301 Zhao Y, Du X, Duan Y, Pan X, Sun Y, You T, Han L, Jin Z, Shang W, Yu J, Guo H, Liu Q, Wu Y, Peng C, Wang J, Zhu C, Yang X, Yang K, Lei Y, Guddat LW, Xu W, Xiao G, Sun L, Zhang L, Rao Z, Yang H. High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors. Protein Cell 2021; 12: 877-888
302 Sa-Ngiamsuntorn K, Suksatu A, Pewkliang Y, Thongsri P, Kanjanasirirat P, Manopwisedjaroen S, Charoensutthivarakul S, Wongtrakoongate P, Pitiporn S, Chaopreecha J, Kongsomros S, Jearawuttanakul K, Wannalo W, Khemawoot P, Chutipongtanate S, Borwornpinyo S, Thitithanyanont A, Hongeng S. Anti-SARS-CoV-2 activity of Andrographis paniculata extract and its major component andrographolide in human lung epithelial cells and cytotoxicity evaluation in major organ cell representatives. J Nat Prod 2021; 84: 1261-1270
303 Shi TH, Huang YL, Chen CC, Pi WC, Hsu YL, Lo LC, Chen WY, Fu SL, Lin CH. Andrographolide and its fluorescent derivative inhibit the main proteases of 2019-nCoV and SARS-CoV through covalent linkage. Biochem Biophys Res Commun 2020; 533: 467-473
304 Alhadrami HA, Sayed AM, Sharif AM, Azhar EI, Rateb ME. Olive-derived triterpenes suppress SARS-CoV-2 main protease: A promising scaffold for future therapeutics. Molecules 2021; 26: 2654
305 Ryu YB, Park SJ, Kim YM, Lee JY, Seo WD, Chang JS, Park KH, Rho MC, Lee WS. SARS-CoV 3CLpro inhibitory effects of quinone-methide triterpenes from Tripterygium regelii . Bioorg Med Chem Lett 2010; 20: 1873-1876
306 van de Sand L, Bormann M, Alt M, Schipper L, Heilingloh CS, Steinmann E, Todt D, Dittmer U, Elsner C, Witzke O, Krawczyk A. Glycyrrhizin effectively inhibits SARS-CoV-2 replication by inhibiting the viral main protease. Viruses 2021; 13: 1-10
307 Srivastava V, Yadav A, Sarkar P. Molecular docking and ADMET study of bioactive compounds of Glycyrrhiza glabra against main protease of SARS-CoV2. Mater Today Proc 2022; 49: 2999-3007
308 Sinha SK, Shakya A, Prasad SK, Singh S, Gurav NS, Prasad RS, Gurav SS. An in-silico evaluation of different saikosaponins for their potency against SARS-CoV-2 using NSP15 and fusion spike glycoprotein as targets. J Biomol Struct Dyn 2020; 39: 1-12
309 Kim TY, Jeon S, Jang Y, Gotina L, Won J, Ju YH, Kim S, Jang MW, Won W, Park MG, Pae AN, Han S, Kim S, Lee CJ. Platycodin D, a natural component of Platycodon grandiflorum, prevents both lysosome- and TMPRSS2-driven SARS-CoV-2 infection by hindering membrane fusion. Exp Mol Med 2021; 53: 956-972
310 Kumar S, Kashyap P, Chowdhury S, Kumar S, Panwar A, Kumar A. Identification of phytochemicals as potential therapeutic agents that binds to Nsp15 protein target of coronavirus (SARS-CoV-2) that are capable of inhibiting virus replication. Phytomedicine 2021; 85: 153317
311 Cho J, Lee YJ, Kim JH, Kim SI, Kim SS, Choi BS, Choi JH. Antiviral activity of digoxin and ouabain against SARS-CoV-2 infection and its implication for COVID-19. Sci Rep 2020; 10: 16200
312 Song YH, Kim DW, Curtis-Long MJ, Yuk HJ, Wang Y, Zhuang N, Lee KH, Jeon KS, Park KH. Papain-like protease (PLpro) inhibitory effects of cinnamic amides from Tribulus terrestris fruits. Biol Pharm Bull 2014; 37: 1021-1028
313 Ahan RE, Hanifehnezhad A, Kehribar E, Oguzoglu TC, Földes K, Özçelik CE, Filazi N, Öztop S, Palaz F, Önder S, Bozkurt EU, Ergünay K, Özkul A, Şeker UÖŞ. A highly potent SARS-CoV-2 blocking lectin protein. ACS Infect Dis 2022; 8: 1253-1264
314 Alsaidi S, Cornejal N, Mahoney O, Melo C, Verma N, Bonnaire T, Chang T, Oʼkeefe BR, Sailer J, Zydowsky TM, Teleshova N, Romero JAF. Griffithsin and carrageenan combination results in antiviral synergy against SARS-CoV-1 and 2 in a pseudoviral model. Mar Drugs 2021; 19: 1-8
315 Cai Y, Xu W, Gu C, Cai X, Qu D, Lu L, Xie Y, Jiang S. 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. Virol Sin 2020; 35: 857-860
316 OʼKeefe BR, Giomarelli B, Barnard DL, Shenoy SR, Chan PKS, McMahon JB, Palmer KE, Barnett BW, Meyerholz DK, Wohlford-Lenane CL, McCray PB. Broad-spectrum in vitro activity and in vivo efficacy of the antiviral protein griffithsin against emerging viruses of the family Coronaviridae . J Virol 2010; 84: 2511-2521
317 Di Pierro F, Derosa G, Maffioli P, Bertuccioli A, Togni S, Riva A, Allegrini P, Khan A, Khan S, Khan BA, Altaf N, Zahid M, Ujjan ID, Nigar R, Khushk MI, Phulpoto M, Lail A, Devrajani BR, Ahmed S. Possible therapeutic effects of adjuvant quercetin supplementation against early-stage COVID-19 infection: a prospective, randomized, controlled, and open-label study. Int J Gen Med 2021; 14: 2359-2366
318 Rondanelli M, Perna S, Gasparri C, Petrangolini G, Allegrini P, Cavioni A, Faliva MA, Mansueto F, Patelli Z, Peroni G, Tartara A, Riva A. Promising effects of 3-month period of Quercetin Phytosome^® supplementation in the prevention of symptomatic COVID-19 disease in healthcare workers: a pilot study. Life 2022; 12: 66
319 Di Pierro F, Iqtadar S, Khan A, Ullah Mumtaz S, Masud Chaudhry M, Bertuccioli A, Derosa G, Maffioli P, Togni S, Riva A, Allegrini P, Khan S. Potential clinical benefits of quercetin in the early stage of COVID-19: Results of a second, pilot, randomized, controlled and open-label clinical trial. Int J Gen Med 2021; 14: 2807-2816
320 McCreary MR, Schnell PM, Rhoda DA. Randomized double-blind placebo-controlled proof-of-concept trial of resveratrol for outpatient treatment of mild coronavirus disease (COVID-19). Sci Rep 2022; 12: 1-12