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Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Natural Agents Modulating ACE-2: A Review of Compounds with Potential against SARS-CoV-2 Infections

Author(s): Arquimedes Gasparotto Junior*, Sara Emília Lima Tolouei, Francislaine Aparecida dos Reis Lívero, Francielli Gasparotto, Thaise Boeing and Priscila de Souza

Volume 27, Issue 13, 2021

Published on: 14 January, 2021

Page: [1588 - 1596] Pages: 9

DOI: 10.2174/1381612827666210114150607

Price: $65


One of the biggest challenges of public health worldwide is reducing the number of events and deaths related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. The angiotensinconverting enzyme 2 (ACE-2), a carboxypeptidase that degrades angiotensin II into angiotensin 1-7, has been identified as a potent receptor for SARS-CoV-2. In the last decades, ACE inhibition has assumed a central role in reducing cardiovascular and renal events. However, with the advent of COVID-19, attention has been turned to ACE-2 as a possible target to reduce virus binding to different human cells. This review aims to discuss recent developments related to the medicinal properties of natural compounds as ACE/ACE-2 inhibitors, which should be highlighted in the future development of studies looking for modulators in SARS-CoV-2 infection. Data show that bioactive compounds isolated from several natural products act by inhibiting ACE/ACE-2, which changes the entire axis of this system. Of the compounds addressed in this review, 7 phenolic compounds, including quercetin, curcumin, naringenin, luteolin, hesperidin, mangiferin, and gallic acid showed binding affinity with molecular ACE-2 target in silico, and 1, esculetin, decreased ACE-2 expression in vivo. Regarding terpenoids and alkaloids, nimbin, withaferin A, andrographolide, zingiberene and, berberine, piperine and thebaine, respectively, showed a binding affinity with molecular ACE-2 target in silico. These findings reinforce the need for future preclinical and clinical studies on these compounds and specific inhibitory effects on ACE-2 of all the other compounds described herein only as nonspecific ACE inhibitors. It is important to mention that some natural compounds such as magnolol, resveratrol, rosmarinic acid, tanshinone IIA, and nicotine have also demonstrated the potential to increase the activity or expression of ACE-2, and could therefore aggravate SARS-CoV-2 infection.

Keywords: Alkaloids, Covid-19, flavonoids, natural products, phenolic compounds, terpenoids.

Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579(7798): 270-3.
[] [PMID: 32015507]
Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020; 8(5): 475-81.
[] [PMID: 32105632]
Fu L, Wang B, Yuan T, et al. Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: A systematic review and meta-analysis. J Infect 2020; 80(6): 656-65.
[] [PMID: 32283155]
Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020; 367(6485): 1444-8.
[] [PMID: 32132184]
Li W, Li J, Hao P, et al. Imbalance between angiotensin II and angiotensin-(1-7) in human coronary atherosclerosis. J Renin Angiotensin Aldosterone Syst 2016; 17(3): 17.
[] [PMID: 27432541]
Patel VB, Zhong JC, Grant MB, Oudit GY. Role of the ACE2/angiotensin 1-7 axis of the renin-angiotensin system in heart failure. Circ Res 2016; 118(8): 1313-26.
[] [PMID: 27081112]
Qaradakhi T, Apostolopoulos V, Zulli A. Angiotensin (1-7) and Alamandine: Similarities and differences. Pharmacol Res 2016; 111: 820-6.
[] [PMID: 27456244]
Simões E Silva AC, Teixeira MM. ACE inhibition, ACE2 and angiotensin-(1-7) axis in kidney and cardiac inflammation and fibrosis. Pharmacol Res 2016; 107: 154-62.
[] [PMID: 26995300]
Brugts JJ, van Vark L, Akkerhuis M, et al. Impact of renin-angiotensin system inhibitors on mortality and major cardiovascular endpoints in hypertension: A number-needed-to-treat analysis. Int J Cardiol 2015; 181: 425-9.
[] [PMID: 25569271]
Bernardi S, Michelli A, Zuolo G, Candido R, Fabris B. Update on RAAS modulation for the treatment of diabetic cardiovascular disease. J Diabetes Res 2016; 2016: 8917578.
Ferrario CM, Mullick AE. Renin angiotensin aldosterone inhibition in the treatment of cardiovascular disease. Pharmacol Res 2017; 125(Pt A): 57-71.
[] [PMID: 28571891]
von Lueder TG, Krum H. RAAS inhibitors and cardiovascular protection in large scale trials. Cardiovasc Drugs Ther 2013; 27(2): 171-9.
[] [PMID: 23224653]
Thomford NE, Senthebane DA, Rowe A, et al. Natural products for drug discovery in the 21st century: Innovations for novel drug discovery. Int J Mol Sci 2018; 19(6): 19.
[] [PMID: 29799486]
Hügel HM, Jackson N, May B, Zhang AL, Xue CC. Polyphenol protection and treatment of hypertension. Phytomedicine 2016; 23(2): 220-31.
[] [PMID: 26926184]
Ma Y, Zeng M, Sun R, Hu M. Disposition of flavonoids impacts their efficacy and safety. Curr Drug Metab 2014; 15(9): 841-64.
[] [PMID: 25658129]
Smith M, Smith JC. Repurposing therapeutics for COVID-19: Supercomputer-based docking to the SARS-CoV-2 viral spike protein and viral spike protein-human ACE2 interface. ChemRxiv 2020; 4.
Maurya VK, Kumar S, Prasad AK, Bhatt MLB, Saxena SK. Structure-based drug designing for potential antiviral activity of selected natural products from Ayurveda against SARS-CoV-2 spike glycoprotein and its cellular receptor. Virusdisease 2020; 31(2): 179-93.
[] [PMID: 32656311]
Colunga Biancatelli RML, Berrill M, Catravas JD, Marik PE. Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19). Front Immunol 2020; 11: 1451.
[] [PMID: 32636851]
Chen L, Li J, Luo C, et al. Binding interaction of quercetin-3-β-galactoside and its synthetic derivatives with SARS-CoV 3CL(pro): structure-activity relationship studies reveal salient pharmacophore features. Bioorg Med Chem 2006; 14(24): 8295-306.
[] [PMID: 17046271]
Muhammad SA, Fatima N. In silico analysis and molecular docking studies of potential angiotensin-converting enzyme inhibitor using quercetin glycosides. Pharmacogn Mag 2015; 11(Suppl. 1): S123-6.
[] [PMID: 26109757]
Huang WY, Fu L, Li CY, Xu LP, Zhang LX, Zhang WM. Quercetin, Hyperin, and Chlorogenic Acid Improve Endothelial Function by Antioxidant, Antiinflammatory, and ACE Inhibitory Effects. J Food Sci 2017; 82(5): 1239-46.
[] [PMID: 28407238]
Luo J, Zhang C, Liu Q, Ou S, Zhang L, Peng X. Combinative effect of sardine peptides and quercetin alleviates hypertension through inhibition of angiotensin I converting enzyme activity and inflammation. Food Res Int 2017; 100(Pt 1): 579-85.
[] [PMID: 28873724]
Adefegha SA, Oyeleye SI, Dada FA, Olasehinde TA, Oboh G. Modulatory effect of quercetin and its glycosylated form on key enzymes and antioxidant status in rats penile tissue of paroxetine-induced erectile dysfunction. Biomed Pharmacother 2018; 107: 1473-9.
[] [PMID: 30257364]
Porzionato A, Emmi A, Barbon S, et al. Sympathetic activation: a potential link between comorbidities and COVID-19. FEBS J 2020; 287(17): 3681-8.
[] [PMID: 32779891]
Matsushita K, Marchandot B, Jesel L, Ohlmann P, Morel O. Impact of COVID-19 on the Cardiovascular System: A Review. J Clin Med 2020; 9(5): 1407.
[] [PMID: 32397558]
Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med 2020; 8(4): e21.
[] [PMID: 32171062]
Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19. N Engl J Med 2020; 382(17): 1653-9.
[] [PMID: 32227760]
Ojeda D, Jiménez-Ferrer E, Zamilpa A, Herrera-Arellano A, Tortoriello J, Alvarez L. Inhibition of angiotensin convertin enzyme (ACE) activity by the anthocyanins delphinidin- and cyanidin-3-O-sambubiosides from Hibiscus sabdariffa. J Ethnopharmacol 2010; 127(1): 7-10.
[] [PMID: 19808084]
Deng YF, Aluko RE, Jin Q, Zhang Y, Yuan LJ. Inhibitory activities of baicalin against renin and angiotensin-converting enzyme. Pharm Biol 2012; 50(4): 401-6.
[] [PMID: 22136493]
Islam R, Parves MR, Paul AS, et al. A molecular modeling approach to identify effective antiviral phytochemicals against the main protease of SARS-CoV-2. J Biomol Struct Dyn 2020; 1-12.
[] [PMID: 32340562]
Ke Z, Su Z, Zhang X, et al. Discovery of a potent angiotensin converting enzyme inhibitor via virtual screening. Bioorg Med Chem Lett 2017; 27(16): 3688-92.
[] [PMID: 28712707]
Utomo RY, Ikawati M, Meiyanto E. Revealing the Potency of Citrus and Galangal Constituents to Halt SARS-CoV-2 Infection. Preprints 2020; 2: 1-8.
Abd Allah ES, Gomaa AMS. Effects of curcumin and captopril on the functions of kidney and nerve in streptozotocin-induced diabetic rats: role of angiotensin converting enzyme 1. Appl Physiol Nutr Metab 2015; 40(10): 1061-7.
[] [PMID: 26398443]
Gao Y, Wang Z, Zhang Y, et al. Naringenin inhibits NG-nitro-L-arginine methyl ester-induced hypertensive left ventricular hypertrophy by decreasing angiotensin-converting enzyme 1 expression. Exp Ther Med 2018; 16(2): 867-73.
[] [PMID: 30112041]
Cheng L, Zheng W, Li M, et al. Citrus fruits are rich in flavonoids for immunoregulation and potential targeting ACE2. Preprints 2020.
Guerrero L, Castillo J, Quiñones M, et al. Inhibition of angiotensin-converting enzyme activity by flavonoids: structure-activity relationship studies. PLoS One 2012; 7(11): e49493.
[] [PMID: 23185345]
Yi L, Li Z, Yuan K, et al. Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells. J Virol 2004; 78(20): 11334-9.
[] [PMID: 15452254]
Al Shukor N, Van Camp J, Gonzales GB, et al. Angiotensin-converting enzyme inhibitory effects by plant phenolic compounds: a study of structure activity relationships. J Agric Food Chem 2013; 61(48): 11832-9.
[] [PMID: 24219111]
Wunpathe C, Potue P, Maneesai P, et al. Hesperidin Suppresses Renin-Angiotensin System Mediated NOX2 Over-Expression and Sympathoexcitation in 2K-1C Hypertensive Rats. Am J Chin Med 2018; 46(4): 751-67.
[] [PMID: 29754503]
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): 766-88.
[] [PMID: 32292689]
Kim EN, Kim MY, Lim JH, et al. The protective effect of resveratrol on vascular aging by modulation of the renin-angiotensin system. Atherosclerosis 2018; 270: 123-31.
[] [PMID: 29407880]
Tiao MM, Lin YJ, Yu HR, et al. Resveratrol ameliorates maternal and post-weaning high-fat diet-induced nonalcoholic fatty liver disease via renin-angiotensin system. Lipids Health Dis 2018; 17(1): 178.
[] [PMID: 30055626]
Moran CS, Biros E, Krishna SM, et al. Resveratrol inhibits growth of experimental abdominal aortic aneurysm associated with upregulation of angiotensin-converting enzyme 2. Arterioscler Thromb Vasc Biol 2017; 37(11): 2195-203.
[] [PMID: 28935757]
Chiou SY, Sung JM, Huang PW, Lin SD. Antioxidant, antidiabetic, and antihypertensive properties of echinacea purpurea flower extract and caffeic acid derivatives using in vitro models. J Med Food 2017; 20(2): 171-9.
[] [PMID: 28061036]
Agunloye OM, Oboh G, Ademiluyi AO, et al. Cardio-protective and antioxidant properties of caffeic acid and chlorogenic acid: Mechanistic role of angiotensin converting enzyme, cholinesterase and arginase activities in cyclosporine induced hypertensive rats. Biomed Pharmacother 2019; 109: 450-8.
[] [PMID: 30399581]
Elfiky AA. Natural products may interfere with SARS-CoV-2 attachment to the host cell. J Biomol Struct Dyn 2020; 1-10.
[] [PMID: 32340551]
Liu Q, Tian J, Xu Y, Li C, Meng X, Fu F. Protective Effect of RA on Myocardial Infarction-Induced Cardiac Fibrosis via AT1R/p38 MAPK Pathway Signaling and Modulation of the ACE2/ACE Ratio. J Agric Food Chem 2016; 64(35): 6716-22.
[] [PMID: 27538767]
Lee J-W, Baek N-I, Lee D-Y. Inhibitory Effects of seco-Triterpenoids from Acanthopanax sessiliflorus Fruits on HUVEC Invasion and ACE Activity. Nat Prod Commun 2015; 10(9): 1517-20.
[] [PMID: 26594747]
Kiss A, Kowalski J, Melzig MF. Compounds from Epilobium angustifolium inhibit the specific metallopeptidases ACE, NEP and APN. Planta Med 2004; 70(10): 919-23.
[] [PMID: 15490319]
Geng F, Yang L, Chou G, Wang Z. Bioguided isolation of angiotensin-converting enzyme inhibitors from the seeds of Plantago asiatica L. Phytother Res 2010; 24(7): 1088-94.
[] [PMID: 19998322]
Kadakol A, Malek V, Goru SK, Pandey A, Bagal S, Gaikwad AB. Esculetin attenuates alterations in Ang II and acetylcholine mediated vascular reactivity associated with hyperinsulinemia and hyperglycemia. Biochem Biophys Res Commun 2015; 461(2): 342-7.
[] [PMID: 25887801]
Chang H, Chang CY, Lee HJ, Chou CY, Chou TC. Magnolol ameliorates pneumonectomy and monocrotaline-induced pulmonary arterial hypertension in rats through inhibition of angiotensin II and endothelin-1 expression. Phytomedicine 2018; 51: 205-13.
[] [PMID: 30466619]
Yazaki K, Arimura GI, Ohnishi T. “Hidden” terpenoids in plants: their biosynthesis, localization and ecological roles. Plant Cell Physiol 2017; 58.
Chen Z zhen, Gong X. Tanshinone IIA contributes to the pathogenesis of endometriosis via renin angiotensin system by regulating the dorsal root ganglion axon sprouting. Life Sci 2020; 240.
Wu H, Li Y, Wang Y, et al. Tanshinone IIA attenuates bleomycin-induced pulmonary fibrosis via modulating angiotensin-converting enzyme 2/ angiotensin-(1-7) axis in rats. Int J Med Sci 2014; 11(6): 578-86.
[] [PMID: 24782646]
Argueta VA, Cano-Asseleih L, Rodarte M. Atlas de las plantas de la medicina tradicional Mexicana. 1st ed. Mexico: Instituto Nacional Indigenista Mexico 1994.
Gutiérrez-Román AS, Gonzalez-Cortazar M, Trejo-Tapia G, et al. Angiotensin-converting enzyme inhibitors from Salvia elegans Vahl. Nat Prod Res 2020; 1-6.
[] [PMID: 32347111]
Kumar A, Choudhir G, Shukla SK, et al. Identification of phytochemical inhibitors against main protease of COVID-19 using molecular modeling approaches. J Biomol Struct Dyn 2020; 1-11.
[PMID: 32448034]
Zheng X, Wang S, Zou X, et al. Ginsenoside Rb1 improves cardiac function and remodeling in heart failure. Exp Anim 2017; 66(3): 217-28.
[] [PMID: 28367863]
Kang DG, Sohn EJ, Kwon EK, Han JH, Oh H, Lee HS. Effects of berberine on angiotensin-converting enzyme and NO/cGMP system in vessels. Vascul Pharmacol 2002; 39(6): 281-6.
[] [PMID: 14567065]
Narkhede RR, Pise A V, Cheke RS, Shinde SD. Recognition of natural products as potential inhibitors of COVID-19 main protease (Mpro): in-silico evidences. Nat Products Bioprospect 2020; 10: 297-306.
Oakes JM, Fuchs RM, Gardner JD, Lazartigues E, Yue X. Nicotine and the renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol 2018; 315(5): R895-906.
[] [PMID: 30088946]
Russo P, Bonassi S, Giacconi R, Malavolta M, Tomino C, Maggi F. COVID-19 and smoking: is nicotine the hidden link? Eur Respir J 2020; 55(6): 55.
[] [PMID: 32341101]
Olds JL, Kabbani N. Is nicotine exposure linked to cardiopulmonary vulnerability to COVID-19 in the general population? FEBS J 2020; 287(17): 3651-5.
[] [PMID: 32189428]
Hamden K, Bengara A, Amri Z, Elfeki A. Experimental diabetes treated with trigonelline: effect on key enzymes related to diabetes and hypertension, β-cell and liver function. Mol Cell Biochem 2013; 381(1-2): 85-94.
[] [PMID: 23754616]
Huang XY, Chen CX. Effect of oxymatrine, the active component from Radix Sophorae flavescentis (Kushen), on ventricular remodeling in spontaneously hypertensive rats. Phytomedicine 2013; 20(3-4): 202-12.
[] [PMID: 23211799]

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