Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Small Molecule Drug Candidates for Managing the Clinical Symptoms of COVID-19: a Narrative Review

  • Yun, Chawon (Department of Pharmacology, School of Medicine, Chungnam National University) ;
  • Lee, Hyun Jae (Smith Liberal Arts College and Department of Addiction Science, Graduate School, Sahmyook University) ;
  • Lee, Choong Jae (Department of Pharmacology, School of Medicine, Chungnam National University)
  • Received : 2021.08.11
  • Accepted : 2021.09.15
  • Published : 2021.11.01
Download PDF
⟨ Previous Next ⟩

Abstract

Towards the end of 2019, an atypical acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in Wuhan, China and subsequently named Coronavirus disease 2019 (COVID-19). The rapid dissemination of COVID-19 has provoked a global crisis in public health. COVID-19 has been reported to cause sepsis, severe infections in the respiratory tract, multiple organ failure, and pulmonary fibrosis, all of which might induce mortality. Although several vaccines for COVID-19 are currently being administered worldwide, the COVID-19 pandemic is not yet effectively under control. Therefore, novel therapeutic agents to eradicate the cause of the disease and/or manage the clinical symptoms of COVID-19 should be developed to effectively regulate the current pandemic. In this review, we discuss the possibility of managing the clinical symptoms of COVID-19 using natural products derived from medicinal plants used for controlling pulmonary inflammatory diseases in folk medicine. Diverse natural products have been reported to exert potential antiviral effects in vitro by affecting viral replication, entry into host cells, assembly in host cells, and release. However, the in vivo antiviral effects and clinical antiviral efficacies of these natural products against SARS-CoV-2 have not been successfully proven to date. Thus, these properties need to be elucidated through further investigations, including randomized clinical trials, in order to develop optimal and ideal therapeutic candidates for COVID-19.

Keywords

Acknowledgement

This research was supported by NRF-2014R1A6A1029617, Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education.

References

  1. Al-Bari, M. A. A. (2017) Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases. Pharmacol. Res. Perspect. 5, e00293. https://doi.org/10.1002/prp2.293
  2. Andersen, P. I., Krpina, K., Ianevski, A., Shtaida, N., Jo, E., Yang, J., Koit, S., Tenson, T., Hukkanen, V., Anthonsen, M. W., Bjoras, M., Evander, M., Winaisch, M. P., Zusinaite, E. and Kainov, D. E. (2019) Novel antiviral activities of obatoclax, emetine, niclosamide, brequinar, and homoharringtonine. Viruses 11, 964. https://doi.org/10.3390/v11100964
  3. Arreola, R., Quintero-Fabian, S., Lopez-Roa, R. I., Flores-Gutierrez, E. O., Reyes-Grajeda, J. P., Carrera-Quintanar, L. and Ortuno-Sahagun, D. (2015) Immunomodulation and anti-inflammatory effects of garlic compounds. J. Immunol. Res. 2015, 401630. https://doi.org/10.1155/2015/401630
  4. Avasarala, S., Zhang, F., Liu, G., Wang, R., London, S. D. and London, L. (2013) Curcumin modulates the inflammatory response and inhibits subsequent fibrosis in a mouse model of viral-induced acute respiratory distress syndrome. PLoS ONE 8, e57285. https://doi.org/10.1371/journal.pone.0057285
  5. Baracco, G. J. (2021) Remdesivir use and hospital length of stay-the paradox of a clinical trial vs real-life use. JAMA Netw. Open 4, e2116057.
  6. Bartoletti, M., Marconi, L., Scudeller, L., Pancaldi, L., Tedeschi, S., Giannella, M., Rinaldi, M., Bussini, L., Valentini, I., Ferravante, A. F., Potalivo, A., Marchionni, E., Fornaro, G., Pascale, R., Pasquini, Z., Puoti, M., Merli, M., Barchiesi, F., Volpato, F., Rubin, A., Saracino, A., Tonetti, T., Gaibani, O., Ranieri, V. M., Viale, P. and Cristini, F.; PREDICO Study Group (2021) Efficacy of corticosteroid treatment for hospitalized patients with severe COVID-19: a multicentre study. Clin. Microbiol. Infect. 27, 105-111. https://doi.org/10.1016/j.cmi.2020.09.014
  7. Bayan, L., Koulivand, P. H. and Gorji, A. (2014) Garlic: a review of potential therapeutic effects. Avicenna J. Phytomed. 4, 1-14.
  8. Berry, M., Fielding, B. and Gamieldien, J. (2015) Potential broad spectrum inhibitors of the coronavirus 3CLpro: a virtual screening and structure-based drug design study. Viruses 7, 6642-6660. https://doi.org/10.3390/v7122963
  9. Bharara, A., Grossman, C., Grinnan, D., Syed, A., Fisher, B., DeWilde, C., Natrajan, R. and Fowler, A. A. (2016) Intravenous vitamin C administered as adjunctive therapy for recurrent acute respiratory distress syndrome. Case Rep. Crit. Care 2016, 8560871.
  10. Breining, P., Frolund, A. L., Hojen, J. F., Gunst, J. D., Staerke, N. B., Saedder, E., Cases-Thomas, M., Little, P., Nielsen, L. P., Sogaard, O. S. and Kjolby, M. (2021) Camostat mesylate against SARSCoV-2 and COVID-19-rationale, dosing and safety. Basic Clin. Pharmacol. Toxicol. 128, 204-212. https://doi.org/10.1111/bcpt.13533
  11. Butt, M. S., Pasha, I., Sultan, M. T., Randhawa, M. A., Saeed, F. and Ahmed, W. (2013) Black pepper and health claims: a comprehensive treatise. Crit. Rev. Food Sci. Nutr. 53, 875-886. https://doi.org/10.1080/10408398.2011.571799
  12. Cao, J., Forrest, J. C. and Zhang, X. A. (2015) A screen of the NIH clinical collection small molecule library identifies potential anti-coronavirus drugs. Antiviral Res. 114, 1-10. https://doi.org/10.1016/j.antiviral.2014.11.010
  13. Cao, Z., Chen, L., Liu, Y. and Peng, T. (2018) Oxysophoridine rescues spinal cord injury via anti-inflammatory, anti-oxidative stress and anti-apoptosis effects. Mol. Med. Rep. 17, 2523-2528.
  14. Cao, Z., Yang, P. and Zhou, Q. (2013) Multiple biological functions and pharmacological effects of lycorine. Sci. China Chem. 56, 1382-1391. https://doi.org/10.1007/s11426-013-4967-9
  15. Carr, A. C. and Maggini, S. (2017) Vitamin C and immune function. Nutrients 9, 1211. https://doi.org/10.3390/nu9111211
  16. Chambial, S., Dwivedi, S., Shukla, K. K., John, P. J. and Sharma, P. (2013) Vitamin C in disease prevention and cure: an overview. Indian J. Clin. Biochem. 28, 314-328. https://doi.org/10.1007/s12291-013-0375-3
  17. Chang, S. J., Chang, Y. C., Lu, K. Z., Tsou, Y. Y. and Lin, C. W. (2012) Antiviral activity of isatis indigotica extract and its derived indirubin against Japanese encephalitis virus. Evid. Based Complement. Alternat. Med. 2012, 925830.
  18. Chen, C. J., Michaelis, M., Hsu, H. K., Tsai, C. C., Yang, K. D., Wu, Y. C., Cinatl, J., Jr. and Doerr, H. S. (2008) Toona sinensis Roem tender leaf extract inhibits SARS coronavirus replication. J. Ethnopharmacol. 120, 108-111. https://doi.org/10.1016/j.jep.2008.07.048
  19. Chen, H., Yang, R., Tang, Y., Xu, J., Feng, Y., Liu, S., Zhang, S. and Hou, L. (2017) Effects of curcumin on pulmonary fibrosis and functions of paraquat-challenged rats. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 29, 973-976.
  20. Chen, L. and Zhao, W. (2016) Apigenin protects against bleomycininduced lung fibrosis in rats. Exp. Ther. Med. 11, 230-234. https://doi.org/10.3892/etm.2015.2885
  21. Chen, Z. and Nakamura, T. (2004) Statistical evidence for the usefulness of Chinese medicine in the treatment of SARS. Phytother. Res. 18, 592-594. https://doi.org/10.1002/ptr.1485
  22. Cheng, P. W., Ng, L. T., Chiang, L. C. and Lin, C. C. (2006) Antiviral effects of saikosaponins on human coronavirus 229E in vitro. Clin. Exp. Pharmacol. Physiol. 33, 612-616. https://doi.org/10.1111/j.1440-1681.2006.04415.x
  23. Chiow, K. H., Phoon, M. C., Putti, T., Tan, B. K. H. and Chow, V. T. (2016) Evaluation of antiviral activities of houttuynia cordata Thunb. extract, quercetin, quercetrin and cinanserin on murine coronavirus and dengue virus infection. Asian Pac. J. Trop. Med. 9, 1-7. https://doi.org/10.1016/j.apjtm.2015.12.002
  24. Chu, C. M., Cheng, V. C., Hung, I. F., Wong, M. M., Chan, K. H., Chan, K. S., Kao, R. Y., Poon, L. L., Wong, C. L., Guan, Y., Peiris, K. S. and Yuen, K. Y.; HKU/UCH SARS Study Group (2004) Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax 59, 252-256. https://doi.org/10.1136/thorax.2003.012658
  25. Cinatl, J., Morgenstern, B., Bauer, G., Chandra, P., Rabenau, H. and Doerr, H. W. (2003) Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet 361, 2045-2046. https://doi.org/10.1016/S0140-6736(03)13615-X
  26. De Clercq, E. (2006) Potential antivirals and antiviral strategies against SARS coronavirus infections. Expert Rev. Anti Infect. Ther. 4, 291-302. https://doi.org/10.1586/14787210.4.2.291
  27. de Wilde, A. H., Zevenhoven-Dobbe, J. C., van der Meer, Y., Thiel, V., Narayanan, K., Makino, S., Snijder, E. J. and van Hemert, M. J. (2011) Cyclosporin A inhibits the replication of diverse coronaviruses. J. Gen. Virol. 92, 2542-2548. https://doi.org/10.1099/vir.0.034983-0
  28. Deng, Y. F., Aluko, R. E., Jin, Q., Zhang, Y. and Yuan, L. J. (2012) Inhibitory activities of baicalin against renin and angiotensin-converting enzyme. Pharm. Biol. 50, 401-406. https://doi.org/10.3109/13880209.2011.608076
  29. Dong, H. J., Wang, Z. H., Meng, W., Li, C. C., Hu, Y. X., Zhou, L. and Wang, X. J. (2018) The natural compound homoharringtonine presents broad antiviral activity in vitro and in vivo. Viruses 10, 601. https://doi.org/10.3390/v10110601
  30. Farazuddin, M., Mishra, R., Jing, Y., Srivastava, V., Comstock, A. T. and Sajjan, U. S. (2018) Quercetin prevents rhinovirus-induced progression of lung disease in mice with COPD phenotype. PLoS ONE 13, e0199612. https://doi.org/10.1371/journal.pone.0199612
  31. Fardet, L. and Feve, B. (2014) Systemic glucocorticoid therapy: a review of its metabolic and cardiovascular adverse events. Drugs 74, 1731-1745. https://doi.org/10.1007/s40265-014-0282-9
  32. Fiore, C., Eisenhut, M., Krausse, R., Ragazzi, E., Pellati, D., Armanini, D. and Bielenberg, J. (2008) Antiviral effects of Glycyrrhiza species. Phytother. Res. 22, 141-148. https://doi.org/10.1002/ptr.2295
  33. Fisher, B. J., Kraskauskas, D., Martin, E. J., Farkas, D., Puri, P., Massey, H. D., Idowu, M. O., Brophy, D. F., Voelkel, N. F., Fowler, A. A., 3rd and Natarajan, R. (2014) Attenuation of sepsis-induced organ injury in mice by vitamin C. J. Parenter. Enter. Nutr. 38, 825-839. https://doi.org/10.1177/0148607113497760
  34. Foolad, F., Aitken, S. L., Shigle, T. L., Prayag, A., Ghantoji, S., ArizaHeredia, E. and Chemaly, R. F. (2019) Oral versus aerosolized ribavirin for the treatment of respiratory syncytial virus infections in hematopoietic cell transplant recipients. Clin. Infect. Dis. 68, 1641-1649. https://doi.org/10.1093/cid/ciy760
  35. Gautam, S. C., Gao, X. and Dulchavsky, S. (2007) Immunomodulation by curcumin. Adv. Exp. Med. Biol. 595, 321-341. https://doi.org/10.1007/978-0-387-46401-5_14
  36. Goletti, D. and Cantini, F. (2021) Baricitinib therapy in covid-19 pneumonia - an unmet need fulfilled. N. Engl. J. Med. 384, 867-869. https://doi.org/10.1056/NEJMe2034982
  37. Gopalakrishnan, S., Ediga, H. H., Reddy, S. S., Reddy, G. B. and Ismail, A. (2018) Procyanidin-B2 enriched fraction of cinnamon acts as a proteasome inhibitor and anti-proliferative agent in human prostate cancer cells. IUBMB Life 70, 445-457. https://doi.org/10.1002/iub.1735
  38. Gu, W., Wang, W., Li, X., Zhang, Y., Wang, L., Yuan, C., Huang, L. and Hao, X. (2015) A novel isocoumarin with anti-influenza virus activity from strobilanthes cusia. Fitoterapia 107, 60-62. https://doi.org/10.1016/j.fitote.2015.10.009
  39. Gustine, J. N. and Jones, D. (2021) Immunopathology of hyperinflammation in COVID-19. Am. J. Pathol. 191, 4-17. https://doi.org/10.1016/j.ajpath.2020.08.009
  40. Gumel, A. B., Iboi, E. A., Ngonghala, C. N. and Ngwa, G. A. (2021) Toward achieving a vaccine-derived herd immunity threshold for COVID-19 in the U.S. Front. Public Health 9, 709369.
  41. He, J., Qi, W. B., Wang, L., Tian, J., Jiao, P. R., Liu, G. Q., Ye, W. C. and Liao, M. (2013) Amaryllidaceae alkaloids inhibit nuclear-to-cytoplasmic export of ribonucleoprotein (RNP) complex of highly pathogenic avian influenza virus H5N1. Influenza Other Respir. Viruses 7, 922-931.
  42. Ho, T., Wu, S., Chen, J., Li, C. and Hsiang, C. (2007) Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction. Antiviral Res. 74, 92-101. https://doi.org/10.1016/j.antiviral.2006.04.014
  43. Ho, Y. L. and Chang, Y. S. (2002) Studies on the antinociceptive, antiinflammatory and anti pyretic effects of Isatis indigotica root. Phytomedicine 9, 419-424. https://doi.org/10.1078/09447110260571661
  44. Hoffmann, M., Schroeder, S., Kleine-Weber, H., Muller, M. A., Drosten, C. and Pohlmann, S. (2020) Nafamostat mesylate blocks activation of SARS-CoV-2: new treatment option for COVID-19. Antimicrob. Agents Chemother. 64, e00754-20.
  45. Hong, J. W., Yang, G. E., Kim, Y. B., Eom, S. H., Lew, J. H. and Kang, H. (2012) Anti-inflammatory activity of cinnamon water extract in vivo and in vitro LPS-induced models. BMC Complement. Altern. Med. 12, 237. https://doi.org/10.1186/1472-6882-12-237
  46. Hong, J. Y., Lee, C. Y., Lee, M. G. and Kim, Y. S. (2018) Effects of dietary antioxidant vitamins on lung functions according to gender and smoking status in Korea: a population-based cross-sectional study. BMJ Open 8, e020656. https://doi.org/10.1136/bmjopen-2017-020656
  47. Hu, S., Dutt, J., Zhao, T. and Foster, C. S. (1997) Tetrandrine potently inhibits herpes simplex virus type-1-induced keratitis in BALB/c mice. Ocul. Immunol. Inflamm. 5, 173-180. https://doi.org/10.3109/09273949709116892
  48. Hu, Z., Lv, Y., Xu, C., Sun, W., Chen, W., Peng, Z., Chen, C., Cui, X., Jiao, D., Cheng, C., Chi, Y., Wei, H., Hu, C., Zeng, Y., Zhang, X. and Yi, Y. (2020) Clinical use of short-course and low-dose corticosteroids in patients with non-severe COVID-19 during pneumonia progression. Front. Public Health 8, 355. https://doi.org/10.3389/fpubh.2020.00355
  49. Hugle, T. (2011) Immunology of fibrotic lung disease: managing infections whilst preventing autoimmunity? J. Inflamm. Res. 4, 21-27. https://doi.org/10.2147/JIR.S10602
  50. Hunt, C., Chakravorty, N. K., Annan, G., Habibzadeh, N. and Schorah, C. J. (1994) The clinical effects of vitamin C supplementation in elderly hospitalised patients with acute respiratory infections. Int. J. Vitam. Nutr. Res. 64, 212-219.
  51. Jang, W. D., Jeon, S., Kim, S. and Lee, S. Y. (2021) Drugs repurposed for COVID-19 by virtual screening of 6,218 drugs and cell-based assay. Proc. Natl. Acad. Sci. U.S.A. 118, e2024302118. https://doi.org/10.1073/pnas.2024302118
  52. Jayaprakasha, G. K. and Rao, L. J. M. (2011) Chemistry, biogenesis, and biological activities of cinnamomum zeylanicum. Crit. Rev. Food Sci. Nutr. 51, 547-562. https://doi.org/10.1080/10408391003699550
  53. Jo, S., Kim, S., Shin, D. H. and Kim, M. S. (2020) Inhibition of SARS-CoV 3CL protease by flavonoids. J. Enzyme Inhib. Med. Chem. 35, 145-151. https://doi.org/10.1080/14756366.2019.1690480
  54. Jurenka, J. S. (2009) Anti-inflammatory properties of curcumin, a major constituent of curcuma longa: a review of preclinical and clinical research. Altern. Med. Rev. 14, 141-153.
  55. Kadam, R. U. and Wilson, I. A. (2017) Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol. Proc. Natl. Acad. Sci. U.S.A. 114, 206-214. https://doi.org/10.1073/pnas.1617020114
  56. Kawatra, P. and Rajagopalan, R. (2015) Cinnamon: mystic powers of a minute ingredient. Pharmacogn. Res. 7, S1-S6.
  57. Khamitov, R. A., Loginova, S., Shchukina, V. N., Borisevich, S. V., Maksimov, V. A. and Shuster, A. M. (2008) Antiviral activity of arbidol and its derivatives against the pathogen of severe acute respiratory syndrome in the cell cultures. Vopr. Virusol. 53, 9-13.
  58. Kim, D., Min, J., Jang, M., Lee, J., Shin, Y., Park, C., Song, J., Kim, H., Kim, S., Jin, Y. H. and Kwon, S. (2019) Natural bis-benzylisoquinoline alkaloids-tetrandrine, fangchinoline, and cepharanthine, inhibit human Coronavirus OC43 infection of MRC-5 human lung cells. Biomolecules 9, 696. https://doi.org/10.3390/biom9110696
  59. Kim, J. E. and Song, Y. J. (2019) Anti-varicella-zoster virus activity of cephalotaxine esters in vitro. J. Microbiol. 57, 74-79. https://doi.org/10.1007/s12275-019-8514-z
  60. Kocaadam, B. and Sanlier, N. (2017) Curcumin, an active component of turmeric (Curcuma longa), and its effects on health. Crit. Rev. Food Sci. Nutr. 57, 2889-2895. https://doi.org/10.1080/10408398.2015.1077195
  61. Krishna, S., Augustin, Y., Wang, J., Xu, C., Staines, H. M., Platteeuw, H., Kamarulzaman, A., Sall, A. and Kremsner, P. (2021) Repurposing antimalarials to tackle the COVID-19 pandemic. Trends Parasitol. 37, 8-11. https://doi.org/10.1016/j.pt.2020.10.003
  62. Kumar, S. and Pandey, A. K. (2013) Chemistry and biological activities of flavonoids: an overview. ScientificWorldJournal 2013, 162750.
  63. La Rosee, F., Bremer, H. C., Gehrke, I., Kehr, A., Hochhaus, A., Birndt, S., Fellhauer, M., Henkes, M., Kumle, B., Russo, S. G. and La Rosee, P. (2020) The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation. Leukemia 34, 1805-1815. https://doi.org/10.1038/s41375-020-0891-0
  64. Lee, C. L., Wang, C. M., Hu, H. C., Yen, H. R., Song, Y. C., Yu, S. J., Chen, C. J., Li, W. C. and Wu, Y. C. (2019) Indole alkaloids indigodoles A-C from aerial parts of strobilanthes cusia in the traditional Chinese medicine qing dai have anti-IL-17 properties. Phytochemistry 162, 39-46. https://doi.org/10.1016/j.phytochem.2019.02.016
  65. Lee, J. C., Kinniry, P. A., Arguiri, E., Serota, M., Kanterakis, S., Chatterjee, S., Solomides, C. C., Javvadi, P., Coumenis., C., Cengel, K. A. and Christofidou-Solomidou, M. (2010) Dietary curcumin increases antioxidant defenses in lung, ameliorates radiation-induced pulmonary fibrosis, and improves survival in mice. Radiat. Res. 173, 590-601. https://doi.org/10.1667/RR1522.1
  66. Lee, Y. Z., Yang, C. W., Hsu, H. Y., Qiu, Y. Q., Yeh, T. K., Chang, H. Y., Chao, Y. S. and Lee, S. J. (2012) Synthesis and biological evaluation of tylophorine-derived dibenzoquinolines as orally active agents: exploration of the role of tylophorine E ring on biological activity. J. Med. Chem. 55, 10363-10377. https://doi.org/10.1021/jm300705j
  67. Li, G. and De Clercq, E. (2020) Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat. Rev. Drug Discov. 19, 149-150. https://doi.org/10.1038/d41573-020-00016-0
  68. Li, S., Chen, C., Zhang, H., Guo, H., Wang, H., Wang, L., Zhang, X., Hua, S., Yu, J., Xiao, P., Li, R. S. and Tan, X. (2005) Identification of natural compounds with antiviral activities against SARS-associated coronavirus. Antiviral Res. 67, 18-23. https://doi.org/10.1016/j.antiviral.2005.02.007
  69. Lin, C. W., Tsai, F. J., Tsai, C. H., Lai, C. C., Wan, L., Ho, T. Y., Hsieh, C. C. and Chao, P. D. L. (2005) Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds. Antiviral Res. 68, 36-42. https://doi.org/10.1016/j.antiviral.2005.07.002
  70. Liou, J. T., Chen, Z. Y., Ho, L. J., Yang, S. P., Chang, D. M., Liang, C. C. and Lai, J. H. (2008) Differential effects of triptolide and tetrandrine on activation of COX-2, NF-κB, and AP-1 and virus production in dengue virus-infected human lung cells. Eur. J. Pharmacol. 589, 288-298. https://doi.org/10.1016/j.ejphar.2008.04.056
  71. Liu, J., Yang, Y., Xu, Y., Ma, C., Qin, C. and Zhang, L. (2011) Lycorine reduces mortality of human enterovirus 71-infected mice by inhibiting virus replication. Virol. J. 8, 483. https://doi.org/10.1186/1743-422X-8-483
  72. Lu, S. and Wang, J. (2014) Homoharringtonine and omacetaxine for myeloid hematological malignancies. J. Hematol. Oncol. 7, 2. https://doi.org/10.1186/1756-8722-7-2
  73. Marefati, N., Eftekhar, N., Kaveh, M., Boskabadi, J., Beheshti, F. and Boskabady, M. H. (2018) The effect of Allium cepa extract on lung oxidant, antioxidant, and immunological biomarkers in ovalbumin-sensitized rats. Med. Princ. Pract. 27, 122-128. https://doi.org/10.1159/000487885
  74. Matsuda, K., Hattori, S., Komizu, Y., Kariya, R., Ueoka, R. and Okada, S. (2014) Cepharanthine inhibited HIV-1 cell-cell transmission and cell-free infection via modification of cell membrane fluidity. Bioorg. Med. Chem. Lett. 24, 2115-2117. https://doi.org/10.1016/j.bmcl.2014.03.041
  75. Menon, V. P. and Sudheer, A. R. (2007) Antioxidant and anti-inflammatory properties of curcumin. Adv. Exp. Med. Biol. 595, 105-125. https://doi.org/10.1007/978-0-387-46401-5_3
  76. Mentre, F., Taburet, J. M., Guedj, J., Anglaret, X., Keita, S., de Lamballerie, X. and Malvy, D. (2015) Dose regimen of favipiravir for Ebola virus disease. Lancet Infect. Dis. 15, 150-151. https://doi.org/10.1016/S1473-3099(14)71047-3
  77. Nathens, A. B., Neff, M. J., Jurkovich, G. J., Klotz, P., Farver, K., Ruzinski, J. T., Radella, F., Garcia, I. and Maier, R. V. (2002) Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann. Surg. 236, 814-822. https://doi.org/10.1097/00000658-200212000-00014
  78. Ni, Y. N., Chen, G., Sun, J., Liang, B. M. and Liang, Z. A. (2019) The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis. Crit. Care 23, 99. https://doi.org/10.1186/s13054-019-2395-8
  79. Park, J. Y., Ko, J. A., Kim, D. W., Kim, Y. M., Kwon, H. J., Jeong, H. J., Kim, C. Y., Park, K. H., Lee, W. S. and Ryu, Y. B. (2016) Chalcones isolated from Angelica keiskei inhibit cysteine proteases of SARSCoV. J. Enzyme Inhib. Med. Chem. 31, 23-30.
  80. Pattanaik, D. S., Hota, D., Prabhakar, P. and Pandhi, P. (2009) Effect of simultaneous administration of piperine on plasma concentration of carbamazepine. Phytother. Res. 12, 264-269.
  81. Pham, L. V., Ngo, H. T. T., Lim, Y. S. and Hwang, S. B. (2012) Hepatitis C virus non-structural 5B protein interacts with cyclin A2 and regulates viral propagation. J. Hepatol. 57, 960-966. https://doi.org/10.1016/j.jhep.2012.07.006
  82. Polansky, H. and Lori, G. (2020) Coronavirus disease 2019 (COVID-19): first indication of efficacy of Gene-Eden-VIR/Novirin in SARS-CoV-2 infection. Int. J. Antimicrob. Agents 55, 105971. https://doi.org/10.1016/j.ijantimicag.2020.105971
  83. Prashanth Goud, M., Bale, S., Pulivendala, G., and Godugu, C. (2019) Therapeutic effects of Nimbolide, an autophagy regulator, in ameliorating pulmonary fibrosis through attenuation of TGF-β1 driven epithelial-to-mesenchymal transition. Int. Immunopharmacol. 75, 105755. https://doi.org/10.1016/j.intimp.2019.105755
  84. Punithavathi, D., Venkatesan, N. and Babu, M. (2000) Curcumin inhibition of bleomycin-induced pulmonary fibrosis in rats. Br. J. Pharmacol. 131, 169-172. https://doi.org/10.1038/sj.bjp.0703578
  85. Qi, Y., Gao, F., Hou, L. and Wan, C. (2017) Anti-inflammatory and immunostimulatory activities of astragalosides. Am. J. Chin. Med. 45, 1157-1167. https://doi.org/10.1142/s0192415x1750063x
  86. Qin, G. W. and Xu, R. S. (1998) Recent advances on bioactive natural products from Chinese medicinal plants. Med. Res. Rev. 18, 375-382. https://doi.org/10.1002/(SICI)1098-1128(199811)18:6<375::AID-MED2>3.0.CO;2-8
  87. Raina, V. and Raina, S. (1980) The responsiveness of leukocyte adenyl cyclase to tylophorine in asthmatic subjects. Biochem. Biophys. Res. Commun. 94, 1074-1077. https://doi.org/10.1016/0006-291X(80)90528-8
  88. Rao, P. V. and Gan, S. H. (2014) Cinnamon: a multifaceted medicinal plant. Evid. Based Complement. Alternat. Med. 2014, 642942.
  89. Rodrigues da Silva, M., Schapochnik, A., Peres Leal, M., Esteves, J., Bichels Hebeda, C., Sandri, S., Pavani, C., Ratto Tempestini Horliana, A. C., Farsky, S. H. P. and Lino-dos-Santos-Franco, A. (2018) Beneficial effects of ascorbic acid to treat lung fibrosis induced by paraquat. PLoS ONE 13, e0205535. https://doi.org/10.1371/journal.pone.0205535
  90. Romero, M., Serrano, M., Efferth, T., Alvarez, M. and Marin, J. (2007) Effect of cantharidin, cephalotaxine and homoharringtonine on "in vitro" models of hepatitis b virus (HBV) and bovine viral diarrhoea virus (BVDV) replication. Planta Med. 73, 552-558. https://doi.org/10.1055/s-2007-967184
  91. Rossignol, J. F. (2016) Nitazoxanide, a new drug candidate for the treatment of middle east respiratory syndrome coronavirus. J. Infect. Public Health 9, 227-230. https://doi.org/10.1016/j.jiph.2016.04.001
  92. Rui, C., Yuxiang, L., Ning, J., Ningtian, M., Qingluan, Z., Yinju, H., Ru, Z., Lin, M., Tao, S. and Jianqiang, Y. (2013) Anti-apoptotic and neuroprotective effects of oxysophoridine on cerebral ischemia both in vivo and in vitro. Planta Med. 79, 916-923. https://doi.org/10.1055/s-0032-1328705
  93. Sakurai, Y., Kolokoltsov, A. A., Chen, C. C., Tidwell, M. W., Bauta, W. E., Klugbauer, N., Grimm, C., Wahl-Schott, C., Biel, M. and Davey, R. A. (2015) Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment. Science 347, 995-998. https://doi.org/10.1126/science.1258758
  94. Savarino, A., Boelaert, J. R., Cassone, A., Majori, G. and Cauda, R. (2003) Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect. Dis. 3, 722-727. https://doi.org/10.1016/S1473-3099(03)00806-5
  95. Schwarz, S., Sauter, D., Wang, K., Zhang, R., Sun, B., Karioti, A., Billa, A. R., Efferth, T. and Schwarz, W. (2014) Kaempferol derivatives as antiviral drugs against the 3a channel protein of coronavirus. Planta Med. 80, 177-182. https://doi.org/10.1055/s-0033-1360277
  96. Schwarz, S., Wang, K., Yu, W. J., Sun, B. and Schwarz, W. (2011) Emodin inhibits current through SARS-associated coronavirus 3a protein. Antiviral Res. 90, 64-69. https://doi.org/10.1016/j.antiviral.2011.02.008
  97. Shahabi, R., Anissian, A., Javadmoosavi, S. A. and Nasirinezhad, F. (2019) Protective and anti-inflammatory effect of selenium nanoparticles against bleomycin-induced pulmonary injury in male rats. Drug Chem. Toxicol. 44, 92-100. https://doi.org/10.1080/01480545.2018.1560466
  98. Shahni, R. and Handique, P. J. (2013) Antibacterial properties of leaf extracts of strobilanthes cusia (Nees) kuntze, a rare ethno-medicinal plant of manipur, India. Int. J. Pharm. Tech. Res. 5, 1281-1285.
  99. Shahwar, D., Raza, M. A., Shafiq-Ur-Rehman, Abbasi, M. A. and AttaUr-Rahman. (2012) An investigation of phenolic compounds from plant sources as trypsin inhibitors. Nat. Prod. Res. 26, 1087-1093. https://doi.org/10.1080/14786419.2011.559637
  100. Shang, A., Cao, S. Y., Xu, X. Y., Gan, R. Y., Tang, G. Y., Corke, H., Mavumengwana, V. and Li, H. B. (2019) Bioactive compounds and biological functions of garlic (Allium sativum L.). Foods 8, 246. https://doi.org/10.3390/foods8070246
  101. Siegel, D., Hui, H. C., Doerffler, E., Clarke, M. O., Chun, K., Zhang, L., Neville, S., Carra, E., Lew, W., Ross, B., Wang, Q., Wolfe, L., Jordan, R., Soloveva, V., Knox, J., Perry, J., Perron, M., Stray, K. M., Barauskas, O., Feng, J. Y., Xu, Y., Lee, G., Rheingold, A. L., Ray, A. S., Bannister, R., Strickley, R., Swaminathan, S., Lee, W. A., Bavari, S., Cihlar, T., Lo, M. K., Warren, T. K. and Mackman, R. L. (2017) Discovery and synthesis of a phosphoramidate prodrug of a pyrrolo[2,1-f][triazin-4-amino] adenine c-nucleoside (GS-5734) for the treatment of Ebola and emerging viruses. J. Med. Chem. 60, 1648-1661. https://doi.org/10.1021/acs.jmedchem.6b01594
  102. Srivastava, R. M., Singh, S., Dubey, S. K., Misra, K. and Khar, A. (2011) Immunomodulatory and therapeutic activity of curcumin. Int. Immunopharmacol. 11, 331-341. https://doi.org/10.1016/j.intimp.2010.08.014
  103. Suleria, H. A. R., Butt, M. S., Anjum, F. M., Saeed, F. and Khalid, N. (2015) Onion: nature protection against physiological threats. Crit. Rev. Food Sci. Nutr. 55, 50-66. https://doi.org/10.1080/10408398.2011.646364
  104. Tanaka, T., Ikeda, T., Kaku, M., Zhu, X. H., Okawa, M., Yokomizo, K., Uyeda, M. and Nohara, T. (2004) A new lignan glycoside and phenylethanoid Glycosides from strobilanthes cusia BREMEK. Chem. Pharm. Bull. 52, 1242-1245. https://doi.org/10.1248/cpb.52.1242
  105. Toyama, M., Hamasaki, T., Uto, T., Aoyama, H., Okamoto, M., Hashmoto, Y. and Baba, M. (2012) Synergistic inhibition of HTLV-1-infected cell proliferation by combination of cepharanthine and a tetramethylnaphthalene derivative. Anticancer Res. 32, 2639-2645.
  106. Tsai, Y. C., Lee, C. L., Yen, H. R., Chang, Y. S., Lin, Y. P., Huang, S. H. and Lin, C. W. (2020) Antiviral action of tryptanthrin isolated from strobilanthes cusia leaf against human coronavirus NL63. Biomolecules 10, 366. https://doi.org/10.3390/biom10030366
  107. Vijayakumar, R. S., Surya, D. and Nalini, N. (2004) Antioxidant efficacy of black pepper (Piper nigrum L.) and piperine in rats with high fat diet induced oxidative stress. Redox Rep. 9, 105-110. https://doi.org/10.1179/135100004225004742
  108. Wan, Z., Lu, Y., Liao, Q., Wu, Y. and Chen, X. (2012) Fangchinoline inhibits human immunodeficiency virus type 1 replication by interfering with gp160 proteolytic processing. PLoS ONE 7, e39225. https://doi.org/10.1371/journal.pone.0039225
  109. Wang, H., Guo, T., Yang, Y., Yu, L., Pan, X. and Li, Y. (2019) Lycorine derivative LY-55 inhibits EV71 and CVA16 replication through downregulating autophagy. Front. Cell. Infect. Microbiol. 9, 277. https://doi.org/10.3389/fcimb.2019.00277
  110. Wang, P., Li, L. F., Wang, Q. Y., Shang, L. Q., Shi, P. Y. and Yin, Z. (2014) Anti-dengue-virus activity and structure-activity relationship studies of lycorine derivatives. ChemMedChem 9, 1522-1533. https://doi.org/10.1002/cmdc.201300505
  111. Wang, Y. S., Li, Y. X., Zhao, P., Wang, H. B., Zhou, R., Hao, Y. J., Wang, J., Wang, S. J., Du, J., Ma, L., Sun, T. and Yu, J. Q. (2015) Anti-inflammation effects of oxysophoridine on cerebral ischemia-reperfusion injury in mice. Inflammation 38, 2259-2268. https://doi.org/10.1007/s10753-015-0211-4
  112. Wang, Y., Lee, S., Ha, Y., Lam, W., Chen, S. R., Dutschman, G. E., Gullen, E. A., Grill, S. P., Cheng, Y., Furstner, A., Francis, S., Baker, D. C., Yang, X., Lee, K. H. and Cheng, Y. C. (2017) Tylophorine analogs allosterically regulates heat shock cognate protein 70 and inhibits hepatitis C virus replication. Sci. Rep. 7, 10037. https://doi.org/10.1038/s41598-017-08815-z
  113. Wintergerst, E. S., Maggini, S. and Hornig, D. H. (2006) Immune-enhancing role of vitamin C and zinc and effect on clinical conditions. Ann. Nutr. Metab. 50, 85-94. https://doi.org/10.1159/000090495
  114. Xu, X., Han, M., Li, T., Sun, W., Wang, D., Fu, B., Zhou, Y., Zheng, X., Yang, Y., Li, X., Zhang, X., Pan, A. and Wei, H. (2020) Effective treatment of severe COVID-19 patients with tocilizumab. Proc. Natl. Acad. Sci. U.S.A. 117, 10970-10975. https://doi.org/10.1073/pnas.2005615117
  115. Yang, C. W., Chuang, T. H., Wu, P. L., Huang, W. H. and Lee, S. J. (2007) Anti-inflammatory effects of 7-methoxycryptopleurine and structure-activity relations of phenanthroindolizidines and phenanthroquinolizidines. Biochem. Biophys. Res. Commun. 354, 942-948. https://doi.org/10.1016/j.bbrc.2007.01.065
  116. Yang, C. W., Lee, Y. Z., Hsu, H. Y., Shih, C., Chao, Y. S., Chang, H. Y. and Lee, S. J. (2017) Targeting coronaviral replication and cellular JAK2 mediated dominant NF-κB activation for comprehensive and ultimate inhibition of Coronaviral activity. Sci. Rep. 7, 4105. https://doi.org/10.1038/s41598-017-04203-9
  117. Yang, C. W., Lee, Y. Z., Kang, I. J., Barnard, D. L., Jan, J. T., Lin, D., Huang, C. W., Yeh, T. K., Chao, Y. S. and Lee, S. J. (2010) 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. 88, 160-168. https://doi.org/10.1016/j.antiviral.2010.08.009
  118. Yang, G., Gao, J., Jia, Y., Yan, L., Yu, J. and Jiang, Y. (2012) Oxysophoridine through intrathecal injection induces antinociception and increases the expression of the GABAAα1 receptor in the spinal cord of mice. Planta Med. 78, 874-880. https://doi.org/10.1055/s-0031-1298471
  119. Yang, Y., Islam, M. S., Wang, J., Li, Y. and Chen, X. (2020) Traditional Chinese medicine in the treatment of patients infected with 2019-new coronavirus (SARS-CoV-2): a review and perspective. Int. J. Biol. Sci. 16,1708-1717. https://doi.org/10.7150/ijbs.45538
  120. Yao, X., Zhang, Y., Long, W. and Liu, P. (2012) Oxysophoridine suppresses the growth of hepatocellular carcinoma in mice: in vivo and cDNA microarray studies. Chin. J. Integr. Med. 18, 209-213. https://doi.org/10.1007/s11655-012-1001-6
  121. 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. and Xu, X. (2004) Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells. J. Virol. 78, 11334-11339. https://doi.org/10.1128/JVI.78.20.11334-11339.2004
  122. You, X., Pan, M., Gao, W., Shiah, H. S., Tao, J., Zhang, D., Koumpouras, F., Wang, S., Zhao, H., Madri, J. A., Baker, D., Cheng, Y. C. and Yin, Z. (2006) Effects of a novel tylophorine analog on collageninduced arthritis through inhibition of the innate immune response. Arthritis Rheum. 54, 877-886. https://doi.org/10.1002/art.21640
  123. Yu, M. S., Lee, J., Lee, J. M., Kim, Y., Chin, Y. W., Jee, J. G., Keum, Y. S. and Jeong, Y. J. (2012) Identification of myricetin and scutella-rein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13. Bioorg. Med. Chem. Lett. 22, 4049-4054. https://doi.org/10.1016/j.bmcl.2012.04.081
  124. Zahedipour, F., Hosseini, S. A., Sathyapalan, T., Majeed, M., Jamial-ahmadi, T., Al-Rasadi, K., Banach, M. and Sahebkar, A. (2020) Potential effects of curcumin in the treatment of COVID-19 infection. Phytother. Res. 34, 2911-2920. https://doi.org/10.1002/ptr.6738
  125. Zhang, X., Cai, Y., Zhang, W. and Chen, X. (2018) Quercetin ameliorates pulmonary fibrosis by inhibiting SphK1/S1P signaling. Biochem. Cell Biol. 96, 742-751. https://doi.org/10.1139/bcb-2017-0302
  126. Zhang, Y. N., Zhang, Q. Y., Li, X. D., Xiong, J., Xiao, S. Q., Wang, Z., Zhang, Z. R., Deng, C. L., Yang, X. L., Wei, H. P., Yuan, Z. M., Ye, H. Q. and Zhang, B. (2020) Gemcitabine, lycorine and oxysophoridine inhibit novel coronavirus (SARS-CoV-2) in cell culture. Emerg. Microbes Infect. 9, 1170-1173. https://doi.org/10.1080/22221751.2020.1772676
  127. Zhou, Y. B., Wang, Y. F., Zhang, Y., Zheng, L. Y., Yang, X. A., Wang, N., Jiang, J. H., Ma, F., Yin, D. T., Sun, C. Y. and Wang, Q. D. (2012) In vitro activity of cepharanthine hydrochloride against clinical wildtype and lamivudine-resistant hepatitis B virus isolates. Eur. J. Pharmacol. 683, 10-15. https://doi.org/10.1016/j.ejphar.2012.02.030
  128. 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, G. F. and Tan, W.; China Novel Coronavirus Investigating and Research Team (2020) A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 382, 727-733. https://doi.org/10.1056/nejmoa2001017