Planta Med 2020; 86(10): 659-664
DOI: 10.1055/a-1177-4396
Natural Product Chemistry and Analytical Studies
Perspectives
Georg Thieme Verlag KG Stuttgart · New York

Challenges at the Time of COVID-19: Opportunities and Innovations in Antivirals from Nature

Andreas Hensel
1   Institute of Pharmaceutical Biology and Phytochemistry, University of Münster, Münster, Germany
,
Rudolf Bauer
2   Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria
,
Michael Heinrich
3   Pharmacognosy and Phytotherapy, UCL School of Pharmacy, London, UK
,
Verena Spiegler
1   Institute of Pharmaceutical Biology and Phytochemistry, University of Münster, Münster, Germany
,
Oliver Kayser
4   Technical Biochemistry, TU Dortmund University, Dortmund, Germany
,
Georg Hempel
5   Institute of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Münster, Münster, Germany
,
Karin Kraft
6   University Medicine Rostock, Chair of Complementary Medicine, Rostock, Germany
› Author Affiliations
Further Information

Publication History

received 20 April 2020
revised 05 May 2020

accepted 13 May 2020

Publication Date:
20 May 2020 (online)

Abstract

As viral infections are an increasing threat to human societies, the need for new therapeutic strategies is becoming even more obvious. As no vaccine is available for COVID-19, the development of directly acting antiviral agents and preventive strategies have to be considered. Nature provides a huge reservoir of anti-infectious compounds, from which we can deduce innovative ideas, therapies, and products. Anti-adhesive natural products interact with the receptor-mediated recognition and early interaction of viruses with the host cells, leading to a reduced internalisation of the virus and reduced infections (e.g., procyanidin-B-2-di-O-gallate against influenza and herpes virus). Lignans like podophyllotoxin and bicyclol show strong antiviral activities against different viruses, and essential oils can directly interact with viral membranes and reduce the hostʼs inflammatory responses (e.g., 1,8-cineol). Echinacea extracts stimulate the immune system, and bioavailable alkamides are key players by interacting with immunomodulating cannabinoid receptors. COVID-19 and SARS-CoV-2 infections have, in part, successfully been treated in China by preparations from traditional Chinese medicine and, while it is too early to draw conclusions, some promising data are available. There is huge potential, but intensified research is needed to develop evidence-based medicines with a clearly defined chemical profile. Intensified research and development, and therefore funding, are needed for exploiting natureʼs reservoir against viral infections. Combined action for basic research, chemistry, pharmacognosy, virology, and clinical studies, but also supply chain, sustainable sourcing, and economic aspects have to be considered. This review calls for intensified innovative science on natural products for the patients and for a healthier world!

 
  • References

  • 1 Wisskirchen K, Lucifora J, Michler T, Protzer U. New pharmacological strategies to fight enveloped viruses. Trends Pharmacol Sci 2014; 35: 470-478
  • 2 Maginnis MS. Virus-receptor interactions: the key to cellular invasion. J Mol Biol 2018; 430: 2590-2611
  • 3 Hsu AC. Influenza virus: a master tactician in innate immune evasion and novel therapeutic interventions. Front Immunol 2018; 9: 743
  • 4 Ezzat K, Pernemalm M, Pålsson S, Roberts TC, Järver P, Dondalska A, Bestas B, Sobkowiak MJ, Levänen B, Sköld M, Thompson EA, Saher O, Kari OK, Lajunen T, Sverremark Ekström E, Nilsson C, Ishchenko Y, Malm T, Wood MJA, Power UF, Masich S, Lindén A, Sandberg JK, Lehtiö J, Spetz AL, El Andaloussi S. The viral protein corona directs viral pathogenesis and amyloid aggregation. Nat Commun 2019; 10: 2331
  • 5 Derksen A, Kühn J, Hafezi W, Sendker J, Ehrhardt C, Ludwig S, Hensel A. Antiviral activity of hydroalcoholic extract from Eupatorium perfoliatum L. against the attachment of influenza A virus. J Ethnopharmacol 2016; 188: 144-152
  • 6 Kim SJ, Lee JW, Eun YG, Lee KH, Yeo SG, Kim SW. Pretreatment with a grape seed proanthocyanidin extract downregulates proinflammatory cytokine expression in airway epithelial cells infected with respiratory syncytial virus. Mol Med Rep 2019; 19: 3330-3336
  • 7 Derksen A, Hensel A, Hafezi W, Herrmann F, Schmidt TJ, Ehrhardt C, Ludwig S, Kühn J. 3-O-galloylated procyanidins from Rumex acetosa L. inhibit the attachment of influenza A virus. PLoS One 2014; 9: e110089
  • 8 Gescher K, Hensel A, Hafezi W, Derksen A, Kühn J. Oligomeric proanthocyanidins from Rumex acetosa L. inhibit the attachment of herpes simplex virus type-1. Antiviral Res 2011; 89: 9-18
  • 9 Gescher K, Kühn J, Hafezi W, Louis A, Derksen A, Deters A, Lorentzen E, Hensel A. Inhibition of viral adsorption and penetration by an aqueous extract from Rhododendron ferrugineum L. as antiviral principle against herpes simplex virus type-1. Fitoterapia 2011; 82: 408-413
  • 10 Gescher K, Kühn J, Lorentzen E, Hafezi W, Derksen A, Deters A, Hensel A. Proanthocyanidin-enriched extract from Myrothamnus flabellifolia Welw. exerts antiviral activity against herpes simplex virus type 1 by inhibition of viral adsorption and penetration. J Ethnopharmacol 2011; 134: 468-474
  • 11 Soares S, Brandão E, García-Estevez I, Fonseca F, Guerreiro C, Ferreira-da-Silva F, Mateus N, Deffieux D, Quideau S, de Freitas V. Interaction between Ellagitannins and salivary proline-rich proteins. J Agric Food Chem 2019; 67: 9579-9590
  • 12 Zálešák F, Bon DJD, Pospíšil J. Lignans and neolignans: Plant secondary metabolites as a reservoir of biologically active substances. Pharmacol Res 2019; 146: 104284
  • 13 Kaplan IW. Condylomata acuminata . New Orl Med Surg J 1942; 94: 388-395
  • 14 Bao XQ, Liu GT. Bicyclol: a novel antihepatitis drug with hepatic heat shock protein 27/70-inducing activity and cytoprotective effects in mice. Cell Stress Chaperones 2008; 13: 347-355
  • 15 Huang MH, Li H, Xue R, Li J, Wang L, Cheng J, Wu Z, Li W, Chen J, Lv X, Li Q, Lan P, Zhao L, Yang Y, Peng Z, Jiang J. Up-regulation of glycolipid transfer protein by bicyclol causes spontaneous restriction of hepatitis C virus replication. Acta Pharm Sin B 2019; 9: 769-781
  • 16 Schröder HC, Merz H, Steffen R, Müller WE, Sarin PS, Trumm S, Schulz J, Eich E. Differential in vitro anti-HIV activity of natural lignans. Z Naturforsch C 1990; 45: 1215-1221
  • 17 Eich E, Pertz H, Kaloga M, Schulz J, Fesen MR, Mazumder A, Pommier Y. (−)-Arctigenin as a lead structure for inhibitors of human immunodeficiency virus type-1 integrase. J Med Chem 1996; 39: 86-95
  • 18 Loizzo MR, Saab AM, Tundis R, Statti GA, Menichini F, Lampronti I, Gambari R, Cinatl J, Doerr HW. Phytochemical analysis and in vitro antiviral activities of the essential oils of seven Lebanon species. Chem Biodivers 2008; 5: 461-470
  • 19 Reichling J, Schnitzler P, Suschke U, Saller R. Essential oils of aromatic plants with antibacterial, antifungal, antiviral, and cytotoxic properties – an overview. Forsch Komplementmed 2009; 16: 79-90
  • 20 Li Y, Lai Y, Wang Y, Liu N, Zhang F, Xu P. 1,8-cineol protect against influenza-virus-induced pneumonia in mice. Inflammation 2016; 39: 1582-1593
  • 21 Nüssing S, Sant S, Koutsakos M, Subbarao K, Nguyen THO, Kedzierska K. Innate and adaptive T cells in influenza disease. Front Med 2018; 12: 34-47
  • 22 Schmidt S, Tramsen L, Rais B, Ullrich E, Lehrnbecher T. Natural killer cells as a therapeutic tool for infectious diseases – current status and future perspectives. Oncotarget 2018; 9: 20891-20907
  • 23 Gyurova IE, Ali A, Waggoner SN. Natural killer cell regulation of B cell responses in the context of viral infection. Viral Immunol 2020; 33: 334-341
  • 24 Bähr I, Spielmann J, Quandt D, Kielstein H. Obesity-associated alterations of natural killer cells and immunosurveillance of cancer. Front Immunol 2020; 11: 245
  • 25 Hui DS, Lee N, Chan PK, Beigel JH. The role of adjuvant immunomodulatory agents for treatment of severe influenza. Antiviral Res 2018; 150: 202-216
  • 26 Nicholls JM, Poon LLM, Lee KC, Ng WF, Lai ST, Leung CY, Chu CM, Hui PK, Mak KL, Lim W, Yan KW, Chan KH, Tsang NC, Guan Y, Yuen KY, Peiris JS. Lung pathology of fatal severe acute respiratory syndrome. Lancet 2003; 361: 1773-1778
  • 27 Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LFP. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol 2020; DOI: 10.1038/s41577-010-0311-8.
  • 28 Wang K, Conlon M, Ren W, Chen BB, Bączek T. Natural products as targeted modulators of the immune system. J Immunol Res 2018; 2018: 7862782
  • 29 Spelman K, Burns J, Nichols D, Winters N, Ottersberg S, Tenborg M. Modulation of cytokine expression by traditional medicines: a review of herbal immunomodulators. Altern Med Rev 2006; 11: 128-150
  • 30 Pleschka S, Stein M, Schoop R, Hudson JB. Anti-viral properties and mode of action of standardized Echinacea purpurea extract against highly pathogenic avian influenza virus (H5N1, H7N7) and Swine-Origin H1N1 (S-OIV). Virol J 2009; 6: 197
  • 31 Park S, Lee MS, Jung S, Lee S, Kwon O, Kreuter MH, Perrinjaquet-Moccetti T, Min B, Yun SH, Kim Y. Echinacea purpurea protects against restraint stress-induced immunosuppression in BALB/c Mice. J Med Food 2018; 21: 261-268
  • 32 Hudson JB. Applications of the phytomedicine Echinacea purpurea (Purple Coneflower) in infectious diseases. J Biomed Biotechnol 2012; 2012: 769896
  • 33 Sharma M, Anderson SA, Schoop R, Hudson JB. Induction of multiple pro-inflammatory cytokines by respiratory viruses and reversal by standardized Echinacea, a potent antiviral herbal extract. Antiviral Res 2009; 83: 165-170
  • 34 Woelkart K, Linde K, Bauer R. Echinacea for preventing and treating the common cold. Planta Med 2008; 74: 633-637
  • 35 Schoop R, Klein P, Suter A, Johnston SL. Echinacea in the prevention of induced rhinovirus colds: a meta-analysis. Clin Ther 2006; 28: 174-183
  • 36 Goel V, Lovlin R, Barton R, Lyon MR, Bauer R, Lee TDG, Basu TK. Efficacy of a standardized echinacea preparation (Echinilin) for the treatment of the common cold: a randomized, double-blind, placebo-controlled trial. J Clin Pharm Ther 2004; 29: 75-83
  • 37 Woelkart K, Bauer R. The role of alkamides as an active principle of echinacea. Planta Med 2007; 73: 615-623
  • 38 Raduner S, Majewska A, Chen JZ, Xie XQ, Hamon J, Faller B, Altmann KH, Gertsch J. Alkylamides from Echinacea are a new class of cannabinomimetics. Cannabinoid type 2 receptor-dependent and -independent immunomodulatory effects. J Biol Chem 2006; 281: 14192-14206
  • 39 World Health Organization (WHO). WHO global report on traditional and complementary medicine 2019. Available at: https://www.who.int/publications-detail/who-global-report-on-traditional-and-complementary-medicine-2019 Accessed May 3, 2020
  • 40 Luo H, Tang QL, Shang YX, Liang SB, Yang M, Robinson N, Liu JP. Can Chinese medicine be used for prevention of Corona virus disease 2019 (COVID-19)? A review of historical classics, research evidence and current prevention programs. Chin J Integr Med 2020; 26: 243-250
  • 41 Leung PC. The efficacy of Chinese medicine for SARS: a review of Chinese publications after the crisis. Am J Chin Med 2007; 35: 575-581
  • 42 Yang Y, Islam MS, Wang J, Li Y, Chen X. Traditional Chinese medicine in the treatment of patients infected with 2019-new Coronavirus (SARS-CoV-2): A review and perspective. Int J Biol Sci 2020; 16: 1708-1717
  • 43 Luo Y, Wang CZ, Hesse-Fong J, Lin JG, Yuan CS. Application of Chinese medicine in acute and critical medical conditions. Am J Chin Med 2019; 47: 1223-1235
  • 44 Ang L, Lee HW, Choi JY, Zhang J, Soo Lee M. Herbal medicine and pattern identification for treating COVID-19: a rapid review of guidelines. Integr Med Res 2020; 9: 100407
  • 45 Li SY, Chen C, Zhang HQ, Guo HY, Wang H, Wang L, Zhang X, Hua SN, Yu J, Xiao PG, Li RS, Tan X. Identification of natural compounds with antiviral activities against SARS-associated coronavirus. Antiviral Res 2005; 67: 18-23
  • 46 Liu S, Wei W, Shi K, Cao X, Zhou M, Liu Z. In vitro and in vivo anti-hepatitis B virus activities of the lignan niranthin isolated from Phyllanthus niruri L. J Ethnopharmacol 2014; 155: 1061-1067
  • 47 Huang RL, Huang YL, Ou JC, Chen CC, Hsu FL, Chang C. Screening of 25 compounds isolated from Phyllanthus species for anti-human hepatitis B virus in vitro . Phytother Res 2003; 17: 449-453
  • 48 Soto-Acosta R, Bautista-Carbajal P, Syed GH, Siddiqui A, Del Angel RM. Nordihydroguaiaretic acid (NDGA) inhibits replication and viral morphogenesis of dengue virus. Antiviral Res 2014; 109: 132-140
  • 49 Merino-Ramos T, Jiménez de Oya N, Saiz JC, Martín-Acebes MA. Antiviral activity of Nordihydroguaiaretic acid and its derivative Tetra-O-Methyl Nordihydroguaiaretic acid against West Nile virus and Zika virus. Antimicrob Agents Chemother 2017; 61: e00376-17
  • 50 Wang S, Le TQ, Kurihara N, Chida J, Cisse Y, Yano M, Kido H. Influenza virus-cytokine-protease cycle in the pathogenesis of vascular hyperpermeability in severe influenza. J Infect Dis 2010; 202: 991-1001
  • 51 Kuo YC, Kuo YH, Lin YL, Tsai WJ. Yatein from Chamaecyparis obtusa suppresses herpes simplex virus type 1 replication in HeLa cells by interruption the immediate-early gene expression. Antiviral Res 2006; 70: 112-120
  • 52 Martinez-Lopez A, Persaud M, Chavez MP, Zhang H, Rong L, Liu S, Wang TT, Sarafianos SG, Diaz-Griffero F. Glycosylated diphyllin as a broad-spectrum antiviral agent against Zika virus. EBioMedicine 2019; 47: 269-283
  • 53 Zhang HJ, Rumschlag-Booms E, Guan YF, Liu KL, Wang DY, Li WF, van Nguyen H, Cuong NM, Soejarto DD, Fong HHS, Rong L. Anti-HIV diphyllin glycosides from Justicia gendarussa . Phytochemistry 2017; 136: 94-100
  • 54 Liu GT. Bicyclol: a novel drug for treating chronic viral hepatitis B and C. Med Chem 2009; 5: 29-43
  • 55 Chen M, Kilgore N, Lee KH, Chen DF. Rubrisandrins A and B, lignans and related anti-HIV compounds from Schisandra rubriflora . J Nat Prod 2006; 69: 1697-1701
  • 56 Li J, Meng AP, Guan XL, Li J, Wu Q, Deng SP, Su XJ, Yang RY. Anti-hepatitis B virus lignans from the root of Streblus asper . Bioorg Med Chem Lett 2013; 23: 2238-2244
  • 57 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