Potential Roles of Phytochemicals in Combating Severe Acute Respiratory Syndrome Coronavirus Infection
DOI:
https://doi.org/10.14719/pst.1525Keywords:
COVID-19, Herbal Drugs, Phytochemicals, Phytomedicine, SARS-CoV-2Abstract
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the causative agent of the current ongoing global pandemic COVID-19 is yet far away from the clutches of contemporary western medicines. With the lack of conventional drugs for this deadly disease the scope for the development of herbal formulations and Ayurvedic medication is finding a sound basis in the current scenario. The past two years has witnessed detailed and focused investigations on the biologically active constituents derived from a range of medicinal plants and their potential antiviral properties against SARS-CoV-2. The promising results of these investigations have intrigued the medical and plant experts in pharmacognosy enough to consider herbal medicines and plant-based products as they are more effective in combating the COVID-19 crisis. However, a large-scale application of the same would require more focused and thorough research on this matter. This review is an attempt to describe the current and future prospects of using medicinal plants and herbal compounds as natural and sustainable alternative for treating COVID-19. The current article evaluates the various strong evidences from biochemical and molecular studies that have been investigated so far in the development of herbal formulations to combat COVID-19 with detailed focus on the most potential phytochemicals of medicinal plants studied in this regard namely Withania somnifera (L.) Dunal, Cinchona officinalis L., Curcuma longa L., Ocimum sanctum L., Azadirachta indica A. Juss., and Tinospora cordifolia (Willd) Miers.
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References
Liu YC, KuoRL, Shih SR. COVID-19: The first documented coronavirus pandemic in history. Biomed. J. 2020; 43:328–333.
Cheng ZJ, Shan J. Novel coronavirus: where we are and what we know. Infection.2019; 48:155-163.
Chandler RE. Serious neurological adverse events after ivermectin-do they occur beyond the indication of onchocerciasis? Am J Trop Med Hyg. 2018; 98(2):382-388.
Adamsick ML, Gandhi RG, Bidell MR. Remdesivir in patients with acute or chronic kidney disease and COVID-19. J Am Soc Nephrol. 2020; 31(7):1384-1386.
Rastogi S, Pandey DN, Singh RH (2020). COVID-19 pandemic: a pragmatic plan for ayurveda intervention. J. Ayurveda Integr. Med.2020; 9475–9476(20):30019–30028. doi:10.1016/j.jaim.2020.04.002
Tabuti JR, Lye KA, Dhillion SS. Traditional herbal drugs of Bulamogi, Uganda: plants, use and administration. Journal of Ethnopharmacology. 2003; 88:19-44.
Ministry of Ayush. Retrieved 24 May 2021; fromhttps://www.ayush.gov.in/ayush-guidelines.html
Parida P, Paul D, Chakravorty D. Nature's therapy for COVID-19: Targeting the vital non-structural proteins (NSP) from SARS-CoV-2 with phytochemicals from Indian medicinal plants. Phytomedicine Plus. 2021; 1(1):100002.https://doi.org/10.1016/j.phyplu.2020.100002
Keyaerts E, Li S, Vijgen L, Rysman E, Verbeeck J, Van Ranst M. Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice. Antimicrob Agents Chemother. 2009; 53: 3416–342. DOI: 10.1128/AAC.01509-08
Ibrahim MAA, Abdelrahman AHM, Hussien TA, Badr EAA, Mohamed TA, ElSeedi HR, Pare PW, Efferth TW, Hegazy MEF. In silico drug discovery of major metabolites from spices as SARS-CoV-2 main protease inhibitors. Comput. Biol. Med. 2020; 126:104046.doi: 10.1016/j.compbiomed.2020.104046.
Pal M, Berhanu G, Desalegn C, et al. Severe acute respiratory syndrome coronavirus2 (SARS-CoV-2): An update. Cureus 2020;12(3): e7423. DOI 10.7759/cureus.7423.
Walls AC, Park YJ, Tortorici, MA, Wall A, McGuire AT, Veesler D. Structure, functions and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell. 2020; 180:281-292.
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li. Y, Wang X, Peng Z. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan. China. Jama. 2020; 323(11): 1061-1069.
Chu DK, Akl EA, Duda S, Solo K, Yaacoub S, Schünemann HJ. Physical distancing, face masks, and eye protection to prevent personto-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis. Lancet. 2020; 395(10242): 1973–1987. doi:10.1016/S0140- 6736(20)31142-9
Yang S, Atkinson S, Wang C, Lee A, Bogoyevitch M, Borg N, Jans D. The broad-spectrum antiviral ivermectin targets the host nuclear transport importin ?/?1 heterodimer. Antiviral Research. 2020; 177: 104760. doi: 10.1016/j.antiviral.2020.104760
Retrieved on 27 January 2022, from https://www.cowin.gov.in/.
Moghadamtousi SZ, Kadir HA, Hassandarvish P, Tajik H, Abubakar S, Zandi K. A review on antibacterial, antiviral, and antifungal activity of curcumin. BioMed Res Int. 2014; 2014:186864.https://doi.org/10.1155/2014/186864.
Cohen MM. Tulsi - Ocimum sanctum: a herb for all reasons. J Ayurveda Integr Med. 2014; 5(4):251e9.https://doi.org/10.4103/0975-9476.146554.
Zumla A, Chan J, Azhar E. Coronaviruses — drug discovery and therapeutic options. Nat Rev Drug Discov. 2016; 15:327–347. https://doi.org/10.1038/nrd.2015.37
Mandlik Ingawale DS, Namdeo AG. Pharmacological evaluation of Ashwagandha highlighting its healthcare claims, safety, and toxicity aspects. J Diet Suppl. 2021; 18(2): 183-226. doi: 10.1080/19390211.2020.1741484.
Tandon N, Yadav S. Safety and clinical effectiveness of Withania somnifera (L.) Dunal root in human ailments. Journal of Ethnopharmacology. 2020; 255: 112768. doi: 10.1016/j.jep.2020.112768
Zhou P, Yang XL, Wang XG. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature.2020;579:270–273 https://doi.org/10.1038/s41586-020-2012-7
Balkrishna A, Pokhrel S, Singh J, Varshney, A. Withanone from Withania somnifera Attenuates SARS-CoV-2 RBD and Host ACE2 interactions to rescue spike protein induced pathologies in humanized zebrafish model. Drug Des Devel Ther. 2021;15: 1111-1133
Vellingiri B, Jayaramayya K, Iyer M, Narayanasamy A, Govindasamy V, Giridharan B. et al. COVID-19: A promising cure for the global panic. Science of The Total Environment. 2020; 725: 138277. doi:https://doi.org/10.1016/j.scitotenv.2020.138277
Astuti I, Ysrsfil. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): An overview of viral structure and host response. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2020; 14(4):407-412. doi: 10.1016/j.dsx.2020.04.020
Jauregui AR, Savalia D, Lowry VK, Farrell CM, Wathelet MG. Identification of residues of SARS-CoV nsp1 that differentially affect inhibition of gene expression and antiviral signaling. PLoS ONE. 2013;8(4): e62416. https://doi.org/10.1371/journal.pone.0062416
Cornillez-Ty C, Liao L, Yates J, Kuhn P, Buchmeier M. Severe acute respiratory syndrome coronavirus nonstructural protein 2 interacts with a host protein complex involved in mitochondrial biogenesis and intracellular signalling. Journal of Virology. 2009; 83(19): 10314-10318. doi: 10.1128/jvi.00842-09
Stobart C, Sexton N, Munjal H, Lu X, Molland K, Tomar S. Chimeric exchange of coronavirus nsp5 proteases (3CLPRO) identifies common and divergent regulatory determinants of protease activity. Journal of Virology. 2013;87(23):12611-12618. doi: 10.1128/jvi.02050-13
Oostra M, te Lintelo E, Deijs M, Verheije M, Rottier P, de Haan C. Localization and membrane topology of coronavirus nonstructural protein 4: involvement of the early secretory pathway in replication. Journal of Virology. 2007; 81(22):12323-12336. doi: 10.1128/jvi.01506-07
Mielech A, Chen Y, Mesecar A, Baker S. Nidovirus papain-like proteases: Multifunctional enzymes with protease, deubiquitinating and deISGylating activities. Virus Research. 2014;194:184-190. doi: 10.1016/j.virusres.2014.01.025
Cottam E, Whelband M, Wileman T. Coronavirus NSP6 restricts autophagosome expansion. Autophagy. 2014; 10(8): 1426-1441. doi: 10.4161/auto.29309
Xiao Y, Ma Q, Restle T, Shang W, Svergun D, Ponnusamy R. et al. Nonstructural proteins 7 and 8 of feline coronavirus form a 2:1 heterotrimer that exhibits primer-independent RNA polymerase activity. Journal of Virology. 2012; 86(8):4444-4454. doi: 10.1128/jvi.06635-11
Tan Y, Fung T, Shen H, Huang M, Liu D. Coronavirus infectious bronchitis virus non-structural proteins 8 and 12 form stable complex independent of the non-translated regions of viral RNA and other viral proteins. Virology. 2018;513:75-84. doi: 10.1016/j.virol.2017.10.004
Miknis Z, Donaldson E, Umland T, Rimmer R, Baric R, Schultz L. Severe acute respiratory syndrome coronavirus NSP9 dimerization is essential for efficient viral growth. Journal of Virology. 2009; 83(7): 3007-3018. doi: 10.1128/jvi.01505-08
Bouvet M, Imbert I, Subissi L, Gluais L, Canard B, Decroly E. RNA 3'-end mismatch excision by the severe acute respiratory syndrome coronavirus nonstructural protein nsp10/nsp14 exoribonuclease complex. Proceedings of The National Academy of Sciences. 2012;109(24): 9372-9377. doi: 10.1073/pnas.1201130109
Fang S, Shen H, Wang J, Tay F, Liu D. Proteolytic processing of polyproteins 1a and 1ab between non-structural proteins 10 and 11/12 of coronavirus infectious bronchitis virus is dispensable for viral replication in cultured cells. Virology. 2008; 379(2): 175-180. doi: 10.1016/j.virol.2008.06.038
Velthuis A, Arnold J, Cameron C, van den Worm S, Snijder, E. The RNA polymerase activity of SARS-coronavirus NSP12 is primer dependent. Nucleic Acids Research. 2009; 38(1): 203-214. doi: 10.1093/nar/gkp904
Ivanov K, Thiel V, Dobbe J, van der Meer Y, Snijder E, Ziebuhr J. Multiple enzymatic activities associated with severe acute respiratory syndrome coronavirus helicase. Journal of Virology. 2004;78(11): 5619-5632. doi: 10.1128/jvi.78.11.5619-5632.2004
Chen P, Jiang M, Hu T, Liu Q, Chen X, Guo D. Biochemical characterization of exoribonuclease encoded by SARS coronavirus. BMB Reports. 2007;40(5): 649-655. doi: 10.5483/bmbrep.2007.40.5.649
Flouchi R, Fikri, Benbrahim K. Prevention of COVID 19 by aromatic and medicinal plants: A systematic review. J. Pharm. Sci and Res. 2020;12(8): 1106-1111.
Wink M. Potential of DNA Intercalating alkaloids and other plant secondary metabolites against SARS-CoV-2 causing COVID-19. Diversity. 2020;12(5): 175. https://doi.org/10.3390/d12050175
Barnard DL, Day CW, Bailey K, Heiner M, Montgomery R, Lauridsen L, et al. Evaluation of immunomodulators, interferons and known in-vitro SARS-CoV inhibitors for inhibition of SARSCoV replication in BALB/c mice. Antiviral Chem Chemother. 2006; 17: 275-284.
Srivastava AK, Chaurasia JP, Khan R, Dhand C, Verma S. Role of medicinal plants of traditional use in recuperating devastating Covid-19 situation. Med Aromat Plants (Los Angeles). 2020; 9: 359. doi: 10.35248/2167-0412.20.9.359.
Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020; 14: 72-73.
Malakar S, Sreelatha L, Dechtawewat T, Noisakran S, Yenchitsomanus PT, Chu JJH, Limjindaporn T. Drug repurposing of quinine as antiviral against dengue virus infection. Virus Res. 2018; 255: 171–178. Doi: 10.1016/j.virusres.2018.07.018.
Jiehe Z, HuxiZazhi H. Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia, Chinese J. Tuberculosis and Respiratory Diseases. 2020; 43: 185-188.
Inklebarger J, Gyer M, Galanis N, Michael M, Adel D. Cinchona bark for the treatment of Covid-19 Pnemonia: A modern review of the potential anti-viral therapeutic applications of an old treatment. International Journal of Medical Science and Clinical Invention. 2020; 7(05): 4795-4801. doi: 10.18535/ijmsci/v7i05.02
Dourado D, Freire D, Pereira D, Amaral-Machado L N, Alencar É, de Barros A, Egito E. Will curcumin nanosystems be the next promising antiviral alternatives in COVID-19 treatment trials? Biomedicine & Pharmacotherapy. 2021; 139: 111578. doi: 10.1016/j.biopha.2021.111578
Srivastava A, Singh D. Destabilizing the structural integrity of SARS-CoV2 receptor proteins by curcumin along with hydroxychloroquine: an insilco approach for a combination therapy. Biological and Medicinal Chemistry April 10, 2020 ChemRxiv. Cambridge: Cambridge Open Engage.
Boroumand N, Samarghandian S, Hashemy SI, Immunomodulatory, anti- inflammatory, and antioxidant effects of curcumin, J. HerbMed Pharm. 2018; 7 (4): 211–219. ?
Allegra A, Innao V, Russo S, Gerace D, Alonci A, Musolino C, Anticancer activity of Curcumin and its analogues: preclinical and clinical studies, Cancer Investig. 2017; 35 (1): 1–22.
Hurley LL, Akinfiresoye L, Nwulia E, Kamiya A, Kulkarni AA, Tizabi Y, Antidepressant-like effects of curcumin in WKY rat model of depression is associated with an increase in hippocampal BDNF, Behav. Brain Res. 2013; 239: 27–30. ?
Praditya D, Kirchhoff L, Bruning J, Rachmawati H, Steinmann J, Steinmann E. Anti-infective properties of the golden spice Curcumin. Front Microbiol. 2019; 10: 912
Zahedipour F, Hosseini SA, Sathyapalan T, Majeed M, Jamialahmadi T, Alrasadi K, B nach M, Sahebkar A. Potential effects of curcumin in the treatment of COVID-19 infection Phytother. Res. 2020; 34(11): 2911-2920.
Zhang L, Lin D, Sun X, Curth U, Drosten C, Sauerhering L, Becker S, Rox K, Hilgenfed R. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved ?-ketoamide inhibitors. Science. 2020; 368 (6489): 409-412
Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough T C, Choe H, Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003; 426(6965): 450–454. https://doi.org/10.1038/nature02145
Gonzalez-Paz LA, Lossada CA, Moncayo LS, Romero F, Paz JL, Vera-Villalobos J, Pérez AE, San-Blas E, Alvarado YJ. Theoretical molecular docking study of the structural disruption of the viral 3CL-protease of COVID19 induced by binding of Capsaicin, Piperine and Curcumin Part 1: a comparative study with chloroquine and hydrochloroquine two antimalaric drugs, Preprint available at Research Square. 2020; https://doi.org/10.21203/rs.3.rs-21206/v1.
Dandapat J, Jena AB, Kanungo N, Nayak V, Chainy CGB. 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, Preprint available at Research Square. 2020; https://doi.org/10.21203/rs.3.rs-22057/v1.
Jamshidi N, Cohen MM. The Clinical Efficacy and Safety of Tulsi in Humans: A systematic review of the literature, evidence-based complementary and alternative medicine: eCAM. 2017; 2017: 9217567. https://doi.org/10.1155/2017/9217567
Chiang LC, Ng LT, Cheng PW, Chiang W, Lin CC. Antiviral activities of extracts and selected pure constituents of Ocimum Basilicum. Clin Exp Pharmacol Physiol. 2005; 32: 811-816.
Goothy S, Goothy S, Choudhary A, Potey G, Chakraborty H, Kumar A et al. Ayurveda’s holistic lifestyle approach for the management of coronavirus disease (COVID-19): Possible role of tulsi. International Journal of Research in Pharmaceutical Sciences. 2020; 11: 16-18. DOI:https://doi.org/10.26452/ijrps.v11iSPL1.1976
Jo S, Kim S, Shin DH, Kim MS. Inhibition of SARS-CoV 3CL protease by flavonoids. J Enzyme Inhib Med Chem.2020;35(1):145-151. doi: 10.1080/14756366.2019.1690480.
Shree, P, Mishra, P, Selvaraj C, Singh S, Chaube, R, Garg N and Tripathi Y. 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. Journal of Biomolecular Structure and Dynamics.2020; 39:1-14. Advance online publication. https://doi.org/10.1080/07391102.2020.1810778
Stower H. Virological assessment of SARS-CoV-2. Nat Med. 2020; 26(4): 465.
Kumar AP, Singh P, Nath NT. Chemistry and bioactivities of essential oils of some Ocimum species: An overview. Asian Pacific Journal of Tropical Biomedicine. 2014; 4(9):682-694.
Ghoke SS, Sood R, Kumar N, Pateriya AK, Bhatia S, Mishra A, Dixit R, Singh VK, Desai D, Kulkarni DD. Et al. Evaluation of antiviral activity of Ocimum sanctum and Acacia rabica leaves extracts against H9N2 virus using embryonated chicken egg model. BMC Complement. Altern. Med. 2018; 18: 174. Doi:10.1186/s12906-018-2238-1
Kumar A. Molecular docking of natural compounds from tulsi (Ocimum sanctum) and neem (Azadirachta indica) against SARS-CoV-2 protein targets. Biology, Engineering, Medicine and Science Reports. 2020; 6(1): 11-13 DOI – 10.5530/bems.6.1.4
Roy S. and Bhattacharyya P. Possible role of traditional medicinal plant Neem (Azadirachta indica) for the management of COVID-19 infection. International Journal of Research in Pharmaceutical Sciences.2020;11(SPL1) :122-125.
Thakurta P, Bhowmik P, Mukherjee S, Hajra T K, Patra A, Bag P K. Antibacterial, antisecretory and antihemorrhagic activity of Azadirachta indica used to treat cholera and diarrhea in India. Journal of Ethnopharmacology. 2007; 111(3): 607–612.
Sithisarn P, Supabphol R, Gritsanapan W. Antioxidant activity of Siamese neem tree (VP1209). Journal of Ethnopharmacology. 2005; 99(1): 109–112.
Baildya N, Khan A, Ghosh N, Dutta T and Chattopadhyay A. Screening of potential drug from Azadirachta indica (Neem) extracts for SARS-CoV-2: An insight from molecular docking and MD-simulation studies. Journal of Molecular Structure. 2021;1227: p.129390.
Arise RO, Acho MA, Yekeen AA, Omokanye IA, Sunday-Nwaso EO, Akiode OS & Malomo SO. Kinetics of angiotensin -1 converting enzyme inhibition and antioxidative properties of Azadirachta indica seed protein hydrolysates. Heliyon. 2019; 5(5): e01747. https://doi.org/10.1016/j.heliyon.2019.e01747
Alzohairy MA. Therapeutics Role of Azadirachta indica (Neem) and their active constituents in diseases prevention and treatment. Evidence-based complementary and alternative medicine: eCAM. 2016; 2016: 7382506. https://doi.org/10.1155/2016/7382506
Nesari TM, Bhardwaj A, ShriKrishna R, Ruknuddin D et al. Neem (Azadirachta Indica A. Juss) Capsules for Prophylaxis of COVID-19 Infection: A Pilot, Double-Blind, Randomized Controlled Trial. Altern Ther Health Med. 2021; 27: 196-203.
Borkotoky S, Banerjee M. A computational prediction of SARS-CoV2 structural protein inhibitors from Azadirachta indica (neem). J. Biomol. Struct. Dyn. 2020; 1–11. doi:10.1080/07391102.2020.1774419
Sarkar L, Putchala RK, Safiriyu AA, and Sarma, JD. Azadirachta indica A. Juss ameliorates mouse hepatitis virus-induced neuroinflammatory demyelination by modulating cell-to-cell fusion in an experimental animal model of multiple sclerosis. Frontiers in Cellular Neuroscience, 2020; 14, 116. https://doi.org/10.3389/fncel.2020.00116
Singh G, Saxena RK. Medicinal properties of Tinospora Cordifolia (Guduchi). Inter J Adv Res, Ideas and Innovations in Technology 2017; 3: 227-231.
Sagar V, Kumar HSA. Efficacy of natural compounds from Tinospora cordifolia against SARS-CoV-2 protease, surface glycoprotein and RNA polymerase. PREPRINT (Version 1) available at Research Square. 2020; [https://doi.org/10.21203/rs.3.rs-27375/v1]
Varshney K, Varshney M, Nath B. Molecular modeling of isolated phytochemicals from Ocimum sanctum towards exploring potential inhibitors of SARS coronavirus main protease and Papain-like protease to treat COVID-19. Available at SSRN: 2020; https://ssrn.com/abstract=3554371
Velu G, Palanichamy V, Rajan AP. Phytochemical and pharmacological importance of plant secondary metabolites in modern medicine. In: Roopan SM, Madhumitha G editors. Bioorganic phase in natural food: An overview Springer; 2018. p. 135–156
Asif M, Saleem M, Saadullah M, Sidra Yaseen HS et al. COVID?19 and therapy with essential oils having antiviral, anti?inflammatory, and immunomodulatory properties. Inflammopharmacology?2020, Aug 14: 1-9 https://doi.org/10.1007/s10787-020-00744-0
Silva JKR, Figueiredo PLB, Byler KG, and 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: 3426; doi:10.3390/ijms21103426.
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