Tamarind (Tamarindus indica L.) Seed a Candidate Protein Source with Potential for Combating SARS-CoV-2 Infection in Obesity

Ana H. de A. Morais; Amanda F. de Medeiros; Isaiane Medeiros; Vanessa C.O. de Lima; Anna B.S. Luz; Bruna L.L. Maciel; Thais S. Passos

doi:10.33393/dti.2021.2192

Authors

Ana H. de A. Morais Biochemistry Postgraduate Biosciences Center, Federal University of Rio Grande do Norte, Natal and Department of Nutrition, Center for Health Sciences, Federal University of Rio Grande do Norte, Natal - Brazil
Amanda F. de Medeiros Biochemistry Postgraduate Biosciences Center, Federal University of Rio Grande do Norte, Natal - Brazil
Isaiane Medeiros Biochemistry Postgraduate Biosciences Center, Federal University of Rio Grande do Norte, Natal - Brazil
Vanessa C.O. de Lima Biochemistry Postgraduate Biosciences Center, Federal University of Rio Grande do Norte, Natal - Brazil
Anna B.S. Luz Biochemistry Postgraduate Biosciences Center, Federal University of Rio Grande do Norte, Natal - Brazil
Bruna L.L. Maciel Nutrition Postgraduate Program, Center for Health Sciences, Federal University of Rio Grande do Norte, Natal and Department of Nutrition, Center for Health Sciences, Federal University of Rio Grande do Norte, Natal - Brazil
Thais S. Passos Department of Nutrition, Center for Health Sciences, Federal University of Rio Grande do Norte, Natal - Brazil

DOI:

https://doi.org/10.33393/dti.2021.2192

Keywords:

COVID-19; ACE-2; FURIN; HNE; inflammation; TMPRSS; 3CL pro .

Abstract

Introduction: Obesity and coronavirus disease (COVID)-19 are overlapping pandemics, and one might worsen the other.

Methods: This narrative review discusses one of the primary mechanisms to initiate acute respiratory distress syndrome, uncontrolled systemic inflammation in COVID-19, and presents a potential candidate for adjuvant treatment. Blocking the S protein binding to angiotensin-converting enzyme 2 (ACE-2) and the 3C-like protease (3CL ^pro) is an effective strategy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Results: Host proteases such as FURIN, trypsin, and transmembrane serine protease 2 (TMPRSS) act in S protein activation. Tamarind trypsin inhibitor (TTI) shows several beneficial effects on the reduction of inflammatory markers (tumor necrosis factor α [TNF-α], leptin) and biochemical parameters (fasting glycemia, triglycerides, and very low-density lipoprotein [VLDL]), in addition to improving pancreatic function and mucosal integrity in an obesity model. TTI may inhibit the action of proteases that collaborate with SARS-CoV-2 infection and the neutrophil activity characteristic of lung injury promoted by the virus.

Conclusion: Thus, TTI may contribute to combating two severe overlapping problems with high cost and social complex implications, obesity and COVID-19.

Downloads

Download data is not yet available.

References

Dietz W, Santos-Burgoa C. Obesity and its implications for COVID-19 Mortality. Obesity (Silver Spring). 2020;28(6):1005. https://doi.org/10.1002/oby.22818 PMID:32237206

Jordan RE, Adab P, Cheng KK. Covid-19: risk factors for severe disease and death. BMJ. 2020;368(March):m1198. https://doi.org/10.1136/bmj.m1198 PMID:32217618

National Academies of Sciences and Medicine E, National Academies of Sciences, Engineering and M. Current Status and Response to the Global Obesity Pandemic: Proceedings of a Workshop—in Brief. (Callahan EA, ed.). The National Academies Press; 2019. https://doi.org/10.17226/25349

Del Rio C, Malani PN. COVID-19—new insights on a rapidly changing epidemic. JAMA. 2020;323(14):1339-1340. https://doi.org/10.1001/jama.2020.3072 PMID:32108857

Gupta R, Ghosh A, Singh AK, Misra A. Clinical considerations for patients with diabetes in times of COVID-19 epidemic. Diabetes Metab Syndr. 2020;14(3):211-212. https://doi.org/10.1016/j.dsx.2020.03.002 PMID:32172175

Pachetti M, Marini B, Benedetti F, et al. Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase variant. J Transl Med. 2020;18(1):179. https://doi.org/10.1186/s12967-020-02344-6 PMID:32321524

Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome main point : hydroxychloroquine was found to be more potent than chloroquine at inhibiting SARS-CoV-2 in vit. Clin Infect Dis. 2020;2:1-25.

Calder PC, Waitzberg DL, Klek S, Martindale RG. Lipids in parenteral nutrition: biological aspects. JPEN J Parenter Enteral Nutr. 2020;44(S1)(suppl 1):S21-S27. https://doi.org/10.1002/jpen.1756 PMID:32049394

Bornstein SR, Dalan R, Hopkins D, Mingrone G, Boehm BO. Endocrine and metabolic link to coronavirus infection. Nat Rev Endocrinol. 2020;16(6):297-298. https://doi.org/10.1038/s41574-020-0353-9 PMID:32242089

Ryan DH, Ravussin E, Heymsfield S. COVID 19 and the patient with obesity—the editors speak out. Obesity (Silver Spring). 2020;28(5):847. https://doi.org/10.1002/oby.22808PMID:32237212

Butler CC, van der Velden AW, Bongard E, et al. Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial. Lancet. 2020;395(10217):42-52. https://doi.org/10.1016/S0140-6736(19)32982-4PMID:31839279

Muscogiuri G, Barrea L, Savastano S, Colao A. Nutritional recommendations for CoVID-19 quarantine. Eur J Clin Nutr. Published online 2020:10-11. https://doi.org/10.1038/s41430-020-0635-2

United Nations System Standing Committee on Nutrition—UNSCN. Food Environments in the COVID-19 Pandemic. UNSCN. Published 2020. https://www.unscn.org/en/news-events/recent-news?idnews=2040. Accessed April 29, 2020.

Rundle AG, Park Y, Herbstman JB, Kinsey EW, Wang YC. COVID-19-related school closings and risk of weight gain among children. Obesity (Silver Spring). 2020;28(6):1008-1009. https://doi.org/10.1002/oby.22813 PMID:32227671

Berger ZD, Evans NG, Phelan AL, Silverman RD. Covid-19: control measures must be equitable and inclusive. BMJ. 2020;368(Sept 2001):m1141. https://doi.org/10.1136/bmj.m1141

Farrell P, Thow AM, Abimbola S, Faruqui N, Negin J. How food insecurity could lead to obesity in LMICs: when not enough is too much: a realist review of how food insecurity could lead to obesity in low- and middle-income countries. Health Promot Int. 2018;33(5):812-826. https://doi.org/10.1093/heapro/dax026 PMID:28541498

Kissler SM, Tedijanto C, Goldstein E, Grad YH, Lipsitch M. Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period. Science. 2020;5793(February 2019):eabb5793. https://doi.org/10.1126/science.abb5793

Pindjakova J, Sartini C, Lo Re O, et al. Gut dysbiosis and adaptive immune response in diet-induced obesity vs. systemic inflammation. Front Microbiol. 2017;8(JUN):1157. https://doi.org/10.3389/fmicb.2017.01157 PMID:28690599

Dixon AE, Peters U. The effect of obesity on lung function. Expert Rev Respir Med. 2018;12(9):755-767. https://doi.org/10.1080/17476348.2018.1506331 PMID:30056777

Johnson AR, Milner JJ, Makowski L. The inflammation highway: metabolism accelerates inflammatory traffic in obesity. Immunol Rev. 2012;249(1):218-238. https://doi.org/10.1111/j.1600-065X.2012.01151.x PMID:22889225

Kassir R. Risk of COVID-19 for patients with obesity. Obes Rev. 2020;21(6):e13034. https://doi.org/10.1111/obr.13034 PMID:32281287

Stefan N. Causes, consequences, and treatment of metabolically unhealthy fat distribution. Lancet Diabetes Endocrinol. 2020;8(7):616-627. https://doi.org/10.1016/S2213-8587(20)30110-8PMID:32559477

Stefan N, Birkenfeld AL, Schulze MB. Global pandemics interconnected—obesity, impaired metabolic health and COVID-19. Nat Rev Endocrinol. 2021;17(3):135-149. https://doi.org/10.1038/s41574-020-00462-1 PMID:33479538

Petersen A, Bressem K, Albrecht J, et al. The role of visceral adiposity in the severity of COVID-19: highlights from a unicenter cross-sectional pilot study in Germany. Metabolism. 2020;110(January):154317. https://doi.org/10.1016/j.metabol.2020.154317 PMID:32673651

Watanabe M, Caruso D, Tuccinardi D, et al. Visceral fat shows the strongest association with the need of intensive care in patients with COVID-19. Metabolism. 2020;111:154319. https://doi.org/10.1016/j.metabol.2020.154319 PMID:32712222

Yang Y, Ding L, Zou X, et al. Visceral adiposity and high intramuscular fat deposition independently predict critical illness in patients with SARS-CoV-2. Obesity (Silver Spring). 2020;28(11):2040-2048. https://doi.org/10.1002/oby.22971 PMID:32677752

Shimomura I, Funahashi T, Takahashi M, et al. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Nat Med. 1996;2(7):800-803. https://doi.org/10.1038/nm0796-800 PMID:8673927

Hazeldine J, Lord JM. Immunesenescence: a predisposing risk factor for the development of COVID-19? Front Immunol. 2020;11(Oct):573662. https://doi.org/10.3389/fimmu.2020.573662 PMID:33123152

Kumar H. Healthy immunity: it’s all about immune regulation. Int Rev Immunol. 2020;39(6):245-246. https://doi.org/10.1080/08830185.2020.1845518 PMID:33275480

Popkin BM, Du S, Green WD, et al. Individuals with obesity and COVID-19: a global perspective on the epidemiology and biological relationships. Obes Rev. 2020;21(11):e13128. https://doi.org/10.1111/obr.13128 PMID:32845580

Ledford H. How obesity could create problems for a COVID vaccine. Nature. 2020;586(7830):488-489. https://doi.org/10.1038/d41586-020-02946-6 PMID:33082543

Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract. 2014;105(2):141-150. https://doi.org/10.1016/j.diabres.2014.04.006 PMID:24798950

do Prado WL, Lofrano MC, Oyama LM, et al. Obesity and inflammatory adipokines: practical implications for exercise prescription. Rev Bras Med Esporte. 2009;15(5):378-383. https://doi.org/10.1590/S1517-86922009000600012

Morais AH de A, Aquino J de S, Silva-Maia JK da, Vale SH de L, Maciel BLL, Passos TS. Nutritional status, diet and viral respiratory infections: perspectives for SARS-CoV-2. Br J Nutr. Published online August 26, 2020:1-32. https://doi.org/10.1017/S0007114520003311

Pillaiyar T, Meenakshisundaram S, Manickam M. Recent discovery and development of inhibitors targeting coronaviruses. Drug Discov Today. 2020;25(4):668-688. https://doi.org/10.1016/j.drudis.2020.01.015 PMID:32006468

Rota PA, Oberste MS, Monroe SS, et al. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science. 2003;300(5624):1394-1399. https://doi.org/10.1126/science.1085952

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(2):106012. https://doi.org/10.1016/j.ijantimicag.2020.106012 PMID:32389723

Forni D, Cagliani R, Clerici M, Sironi M. Molecular evolution of human coronavirus genomes. Trends Microbiol. 2017;25(1):35-48. https://doi.org/10.1016/j.tim.2016.09.001PMID:27743750

Liu Y, Liang C, Xin L, et al. The development of coronavirus 3C-like protease (3CLpro) inhibitors from 2010 to 2020. Eur J Med Chem. 2020;206:112711. https://doi.org/10.1016/j.ejmech.2020.112711 PMID:32810751

Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. Published online 2020:1-10. https://doi.org/10.1016/j.cell.2020.02.052

Xu XW, Wu XX, Jiang XG, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ. 2020;368(Jan):m606. https://doi.org/10.1136/bmj.m606 PMID:32075786

Simões e Silva AC, Silveira KD, Ferreira AJ, Teixeira MM. ACE2, angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis. Br J Pharmacol. 2013;169(3):477-492. https://doi.org/10.1111/bph.12159 PMID:23488800

Santos RAS, Ferreira AJ, Simões E, Silva AC, Silva AC. Recent advances in the angiotensin-converting enzyme 2-angiotensin(1-7)-Mas axis. Exp Physiol. 2008;93(5):519-527. https://doi.org/10.1113/expphysiol.2008.042002 PMID:18310257

Ferreira AJ, Santos RAS, Bradford CN, et al. Therapeutic implications of the vasoprotective axis of the renin-angiotensin system in cardiovascular diseases. Hypertension. 2010;55(2):207-213. https://doi.org/10.1161/HYPERTENSIONAHA.109.140145 PMID:20038757

Santos PCJL, Krieger JE, Pereira AC. Renin-angiotensin system, hypertension, and chronic kidney disease: pharmacogenetic implications. J Pharmacol Sci. 2012;120(2):77-88. https://doi.org/10.1254/jphs.12R03CR PMID:23079502

Shinozaki K, Ayajiki K, Nishio Y, Sugaya T, Kashiwagi A, Okamura T. Evidence for a causal role of the renin-angiotensin system in vascular dysfunction associated with insulin resistance. Hypertension. 2004;43(2 I):255-262. https://doi.org/10.1161/01.HYP.0000111136.86976.26

Engeli S, Negrel R, Sharma AM. Physiology and pathophysiology of the adipose tissue renin-angiotensin system. Hypertension. 2000;35(6):1270-1277. https://doi.org/10.1161/01.HYP.35.6.1270 PMID:10856276

Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6(1):16. https://doi.org/10.1038/s41421-020-0156-0 PMID:32194981

Roca-Ho H, Riera M, Palau V, Pascual J, Soler MJ. Characterization of ACE and ACE2 expression within different organs of the NOD mouse. Int J Mol Sci. 2017;18(3):E563. https://doi.org/10.3390/ijms18030563 PMID:28273875

Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-1034. https://doi.org/10.1016/S0140-6736(20)30628-0 PMID:32192578

Al Heialy S, Hachim MY, Senok A, et al. Regulation of angiotensin converting enzyme 2 (ACE2) in obesity: implications for COVID-19. bioRxiv. 2020;2:2020.04.17.046938. https://doi.org/10.1101/2020.04.17.046938

Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. JAMA. 2020;323(18):1824-1836. https://doi.org/10.1001/jama.2020.6019 PMID:32282022

Mamber S, Krakowka S, Osborn J, et al. Could unconventional immunomodulatory agents help alleviate COVID-19 symptoms and severity? Preprints. 2020;(April). https://doi.org/10.20944/preprints202004.0014.v1

He J, Hu L, Huang X, et al. Potential of coronavirus 3C-like protease inhibitors for the development of new anti-SARS-CoV-2 drugs: insights from structures of protease and inhibitors. Int J Antimicrob Agents. 2020;56(2):106055. https://doi.org/10.1016/j.ijantimicag.2020.106055PMID:32534187

Farady CJ, Craik CS. Mechanisms of macromolecular protease inhibitors. Clin Lymphoma. 2010;11(17):19-222341-222346. https://doi.org/10.1002/cbic.201000442

Laskowski M Jr, Kato I. Protein inhibitors of proteinases. Annu Rev Biochem. 1980;49(1):593-626. https://doi.org/10.1146/annurev.bi.49.070180.003113 PMID:6996568

Barkia I, Ketata Bouaziz H, Sellami Boudawara T, Aleya L, Gargouri AF, Saari N. Acute oral toxicity study on Wistar rats fed microalgal protein hydrolysates from Bellerochea malleus. Environ Sci Pollut Res Int. 2020;27(16):19087-19094. https://doi.org/10.1007/s11356-018-4007-6PMID:30612348

Souza DD, Brandão-Costa RMP, Albuquerque WWC, Porto ALF. Partial purification and characterization of a trypsin inhibitor isolated from Adenanthera pavonina L. seeds. S Afr J Bot. 2016;104:30-34. https://doi.org/10.1016/j.sajb.2015.11.008

Cristina Oliveira de Lima V, Piuvezam G, Leal Lima Maciel B, Heloneida de Araújo Morais A. Trypsin inhibitors: promising candidate satietogenic proteins as complementary treatment for obesity and metabolic disorders? J Enzyme Inhib Med Chem. 2019;34(1):405-419. https://doi.org/10.1080/14756366.2018.1542387 PMID:30734596

Lewis GP. Lista de Espécies da Flora do Brasil. Jardim Botânico do Rio de Janeiro. https://doi.org/10.3109/13880209209053984

Ribeiro JA, Serquiz AC, Silva PF, et al. Trypsin inhibitor from Tamarindus indica L. seeds reduces weight gain and food consumption and increases plasmatic cholecystokinin levels. Clinics (São Paulo). 2015;70(2):136-143. https://doi.org/10.6061/clinics/2015(02)11 PMID:25789523

Carvalho FMCC, Lima VCOO, Costa IS, et al. A trypsin inhibitor from tamarind reduces food intake and improves inflammatory status in rats with metabolic syndrome regardless of weight loss. Nutrients. 2016;8(10):1-14. https://doi.org/10.3390/nu8100544 PMID:27690087

Costa IS, Medeiros AF, Carvalho FMC, et al. Satietogenic protein from tamarind seeds decreases food intake, leptin plasma and CCK-1r gene expression in obese wistar rats. Obes Facts. 2018;11(6):440-453. https://doi.org/10.1159/000492733 PMID:30537704

Luz ABS, Dos Santos Figueredo JB, Salviano BDPD, et al. Adipocytes and intestinal epithelium dysfunctions linking obesity to inflammation induced by high glycemic index pellet-diet in Wistar rats. Biosci Rep. 2018;38(3):1-15. https://doi.org/10.1042/BSR20180304PMID:29950343

Li S, Liu L, He G, Wu J. Molecular targets and mechanisms of bioactive peptides against metabolic syndromes. Food Funct. 2018;9(1):42-52. https://doi.org/10.1039/C7FO01323JPMID:29188845

De Queiroz JLC, De Araújo Costa RO, Rodrigues Matias LL, et al. Chitosan-whey protein nanoparticles improve encapsulation efficiency and stability of a trypsin inhibitor isolated from Tamarindus indica L. Food Hydrocoll. 2018;84:247-256. https://doi.org/10.1016/j.foodhyd.2018.06.010

Costa ROA. Identification of safety and potential clinical application of nanoparticles loaded with a trypsin inhibitor isolated from tamarind seeds (Tamarindus indica L.). Dissertation. Published online 2019. https://repositorio.ufrn.br/jspui/handle/123456789/27159

Matias LLR, Costa ROA, Passos TS, et al. Tamarind trypsin inhibitor in chitosan-whey protein nanoparticles reduces fasting blood glucose levels without compromising insulinemia: a preclinical study. Nutrients. 2019;11(11):2770. https://doi.org/10.3390/nu11112770PMID:31739532

Santos EA, Oliveira AS, Arajo Rablo LM, Ferreira A, Arajo Morais AH. Affinity chromatography as a key tool to purify protein protease inhibitors from plants. In: Affinity Chromatography. InTech; 2012:35. https://doi.org/10.5772/34982

Medeiros AF, Costa IS, Carvalho FMC, et al. Biochemical characterisation of a Kunitz-type inhibitor from Tamarindus indica L. seeds and its efficacy in reducing plasma leptin in an experimental model of obesity. J Enzyme Inhib Med Chem. 2018;33(1):334-348. https://doi.org/10.1080/14756366.2017.1419220 PMID:29322840

Carvalho FMC, Lima VCO, Costa IS, et al. Anti-TNF-α agent tamarind kunitz trypsin inhibitor improves lipid profile of wistar rats presenting dyslipidemia and diet-induced obesity regardless of PPAR-γ induction. Nutrients. 2019;11(3):E512. https://doi.org/10.3390/nu11030512PMID:30818882

Winer DA, Luck H, Tsai S, Winer S. The intestinal immune system in obesity and insulin resistance. Cell Metab. 2016;23(3):413-426. https://doi.org/10.1016/j.cmet.2016.01.003PMID:26853748

Maurizi G, Della Guardia L, Maurizi A, Poloni A. Adipocytes properties and crosstalk with immune system in obesity-related inflammation. J Cell Physiol. 2018;233(1):88-97. https://doi.org/10.1002/jcp.25855 PMID:28181253

Adeyemo SM, Onilude AA. Enzymatic reduction of anti-nutritional factors in fermenting soybeans by Lactobacillus plantarum isolates from fermenting cereals. Niger Food J. 2013;31(2):84-90. https://doi.org/10.1016/S0189-7241(15)30080-1

De Blasio MJ, Boije M, Kempster SL, et al. Leptin matures aspects of lung structure and function in the ovine fetus. Endocrinology. 2016;157(1):395-404. https://doi.org/10.1210/en.2015-1729 PMID:26479186

Torday JS, Powell FL, Farmer CG, Orgeig S, Nielsen HC, Hall AJ. Leptin integrates vertebrate evolution: from oxygen to the blood-gas barrier. Respir Physiol Neurobiol. 2010;173(1)(suppl):S37-S42. https://doi.org/10.1016/j.resp.2010.01.007 PMID:20096383

Bassi M, Furuya WI, Menani JV, et al. Leptin into the ventrolateral medulla facilitates chemorespiratory response in leptin-deficient (ob/ob) mice. Acta Physiol (Oxf). 2014;211(1):240-248. https://doi.org/10.1111/apha.12257 PMID:24521430

Sideleva O, Dixon AE. The many faces of asthma in obesity. J Cell Biochem. 2014;115(3):421-426. https://doi.org/10.1002/jcb.24678 PMID:24115053

Sood A, Ford ES, Camargo CA Jr. Association between leptin and asthma in adults. Thorax. 2006;61(4):300-305. https://doi.org/10.1136/thx.2004.031468 PMID:16540481

Fook JMSLL, Macedo LLP, Moura GEDD, et al. A serine proteinase inhibitor isolated from Tamarindus indica seeds and its effects on the release of human neutrophil elastase. Life Sci. 2005;76(25):2881-2891. https://doi.org/10.1016/j.lfs.2004.10.053 PMID:15820500

Ribeiro JKC, Cunha DDS, Fook JMSLL, Sales MP. New properties of the soybean trypsin inhibitor: inhibition of human neutrophil elastase and its effect on acute pulmonary injury. Eur J Pharmacol. 2010;644(1-3):238-244. https://doi.org/10.1016/j.ejphar.2010.06.067PMID:20624384

Thanigaimalai P, Konno S, Yamamoto T, et al. Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds: design, synthesis, biological evaluation, and docking studies. Eur J Med Chem. 2013;68:372-384. https://doi.org/10.1016/j.ejmech.2013.07.037 PMID:23994330

Elfiky AA. Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): a molecular docking study. Life Sci. 2020;253(February):117592. https://doi.org/10.1016/j.lfs.2020.117592 PMID:32222463

Wu C, Liu Y, Yang Y, et al. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm Sin B. 2020;10(5):766-788. https://doi.org/10.1016/j.apsb.2020.02.008 PMID:32292689