{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T11:34:36Z","timestamp":1790508876614,"version":"4.1.0"},"reference-count":135,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2020,9,1]],"date-time":"2020-09-01T00:00:00Z","timestamp":1598918400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Rector of Universitas Padjadjaran","award":["1733\/UN6.3.1\/LT\/2020"],"award-info":[{"award-number":["1733\/UN6.3.1\/LT\/2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Over the years, coronaviruses (CoV) have posed a severe public health threat, causing an increase in mortality and morbidity rates throughout the world. The recent outbreak of a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the current Coronavirus Disease 2019 (COVID-19) pandemic that affected more than 215 countries with over 23 million cases and 800,000 deaths as of today. The situation is critical, especially with the absence of specific medicines or vaccines; hence, efforts toward the development of anti-COVID-19 medicines are being intensively undertaken. One of the potential therapeutic targets of anti-COVID-19 drugs is the angiotensin-converting enzyme 2 (ACE2). ACE2 was identified as a key functional receptor for CoV associated with COVID-19. ACE2, which is located on the surface of the host cells, binds effectively to the spike protein of CoV, thus enabling the virus to infect the epithelial cells of the host. Previous studies showed that certain flavonoids exhibit angiotensin-converting enzyme inhibition activity, which plays a crucial role in the regulation of arterial blood pressure. Thus, it is being postulated that these flavonoids might also interact with ACE2. This postulation might be of interest because these compounds also show antiviral activity in vitro. This article summarizes the natural flavonoids with potential efficacy against COVID-19 through ACE2 receptor inhibition.<\/jats:p>","DOI":"10.3390\/molecules25173980","type":"journal-article","created":{"date-parts":[[2020,9,1]],"date-time":"2020-09-01T14:21:10Z","timestamp":1598970070000},"page":"3980","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":98,"title":["Natural Flavonoids as Potential Angiotensin-Converting Enzyme 2 Inhibitors for Anti-SARS-CoV-2"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6156-8025","authenticated-orcid":false,"given":"Muchtaridi","family":"Muchtaridi","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Jl Raya 21.5, Bandung-Sumedang 45363, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Fauzi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Jl Raya 21.5, Bandung-Sumedang 45363, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4953-927X","authenticated-orcid":false,"given":"Nur Kusaira","family":"Khairul Ikram","sequence":"additional","affiliation":[{"name":"Institute of Biological Sciences, Faculty of Science, Universiti Malaya, Kuala Lumpur 50603, Malaysia"},{"name":"Centre for Research in Biotechnology for Agriculture (CEBAR), Universiti Malaya, Kuala Lumpur 50603, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amirah","family":"Mohd Gazzali","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Penang, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Habibah A.","family":"Wahab","sequence":"additional","affiliation":[{"name":"Pharmaceutical Design and Simulation Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Penang, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,1]]},"reference":[{"key":"ref_1","first-page":"63","article-title":"Corona virus SARS-CoV-2 disease COVID-19: Infection, prevention and clinical advances of the prospective chemical drug therapeutics","volume":"7","author":"Chhikara","year":"2020","journal-title":"Chem. Biol. Lett."},{"key":"ref_2","unstructured":"World Health Organization (2020, May 02). Coronavirus Disease 2019 (COVID-19) Situation Report\u201470. Available online: https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019\/situation-reports\/."},{"key":"ref_3","unstructured":"World Health Organization (2020, April 23). WHO Director-General\u2019s Opening Remarks at the Media Briefing on COVID-19\u201411 March 2020. Available online: https:\/\/www.who.int\/dg\/speeches\/detail\/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020."},{"key":"ref_4","first-page":"1","article-title":"Polarization and public health: Partisan differences in social distancing during the Coronavirus pandemic","volume":"20","author":"Allcott","year":"2020","journal-title":"NBER Work. Pap."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2372","DOI":"10.1016\/j.jacc.2020.03.021","article-title":"Catheterization laboratory considerations during the coronavirus (COVID-19) pandemic: From ACC\u2019s Interventional Council and SCAI","volume":"75","author":"Welt","year":"2020","journal-title":"J. Am. Coll Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1056\/NEJMoa2001017","article-title":"A novel coronavirus from patients with pneumonia in China, 2019","volume":"382","author":"Zhu","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_7","first-page":"1","article-title":"Real-time tentative assessment of the epidemiological characteristics of novel coronavirus infections in Wuhan, China, as at 22 January 2020","volume":"25","author":"Wu","year":"2020","journal-title":"Eur. Commun. Dis. Bull."},{"key":"ref_8","first-page":"7","article-title":"Coronavirus COVID-19: Available free literature provided by various companies, journals and organizations around the world","volume":"5","author":"Nadeem","year":"2020","journal-title":"J. Ongoing Chem. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.3390\/v4061011","article-title":"Mechanisms of coronavirus cell entry mediated by the viral spike protein","volume":"4","author":"Belouzard","year":"2012","journal-title":"Viruses"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Huang, J., Song, W., Huang, H., and Sun, Q. (2020). Pharmacological therapeutics targeting RNA-dependent RNA polymerase, proteinase and spike protein: From mechanistic studies to clinical trials for COVID-19. J. Clin. Med., 9.","DOI":"10.3390\/jcm9041131"},{"key":"ref_11","first-page":"115","article-title":"Quaternary Structure of the SARS Coronavirus Main Protease","volume":"Volume 1","author":"Sunil","year":"2009","journal-title":"Molecular Biology of the SARS-Coronavirus"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1161\/CIRCRESAHA.120.317015","article-title":"Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: Celebrating the 20th anniversary of the discovery of ACE2","volume":"126","author":"Gheblawi","year":"2020","journal-title":"Circ. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"109782","DOI":"10.1016\/j.mehy.2020.109782","article-title":"Purposing Saikosaponins for the treatment of COVID-19","volume":"140","author":"Bahbah","year":"2020","journal-title":"Med. Hypoth."},{"key":"ref_14","first-page":"185","article-title":"Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia (in Chinnese)","volume":"43","author":"Jiang","year":"2020","journal-title":"Chin. J. Tuberc. Respir. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"72","DOI":"10.5582\/bst.2020.01047","article-title":"Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies","volume":"14","author":"Gao","year":"2020","journal-title":"Biosci. Trends"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"105949","DOI":"10.1016\/j.ijantimicag.2020.105949","article-title":"Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial","volume":"56","author":"Gautret","year":"2020","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_17","first-page":"215","article-title":"A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19) (in Chinese)","volume":"49","author":"Chen","year":"2020","journal-title":"J. Zhejiang Univ. (Med. Sci.)"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Cao, Y.-c., Deng, Q.-x., and Dai, S.-x. (2020). Remdesivir for severe acute respiratory syndrome coronavirus 2 causing COVID-19: An evaluation of the evidence. Travel Med. Infect. Dis., 101647.","DOI":"10.1016\/j.tmaid.2020.101647"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2327","DOI":"10.1056\/NEJMoa2007016","article-title":"Compassionate use of remdesivir for patients with severe Covid-19","volume":"382","author":"Grein","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Cai, Q., Yang, M., Liu, D., Chen, J., Shu, D., Xia, J., Liao, X., Gu, Y., Cai, Q., and Yang, Y. (2020). Experimental treatment with favipiravir for COVID-19: An open-label control study. Engineering, in press.","DOI":"10.1016\/j.eng.2020.03.007"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.jmii.2020.03.034","article-title":"Treatment options for COVID-19: The reality and challenges","volume":"53","author":"Jean","year":"2020","journal-title":"J. Microbiol. Immunol. Infect."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e40","DOI":"10.26633\/RPSP.2020.40","article-title":"Clinical trials on drug repositioning for COVID-19 treatment","volume":"44","author":"Rosa","year":"2020","journal-title":"Rev. Panam Salud Publica"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"102097","DOI":"10.1016\/j.msard.2020.102097","article-title":"Immunosuppression during the COVID-19 pandemic in neuromyelitis optica spectrum disorders patients: A new challenge","volume":"41","author":"Correa","year":"2020","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Islam, M.T., Sarkar, C., El-Kersh, D.M., Jamaddar, S., Uddin, S.J., Shilpi, J.A., and Mubarak, M.S. (2020). Natural products and their derivatives against coronavirus: A review of the non-clinical and pre-clinical data. Phytother. Res., 1\u201322.","DOI":"10.1002\/ptr.6700"},{"key":"ref_25","first-page":"1","article-title":"Tocilizumab for patients with COVID-19 pneumonia. The TOCIVID-19 phase 2 trial","volume":"6","author":"Perrone","year":"2020","journal-title":"medRxiv"},{"key":"ref_26","first-page":"e000878","article-title":"Insights from immuno-oncology: The Society for Immunotherapy of Cancer Statement on access to IL-6-targeting therapies for COVID-19","volume":"8","author":"Ascierto","year":"2020","journal-title":"J. Immunol. Ther. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1016\/S0140-6736(20)31022-9","article-title":"Remdesivir in adults with severe COVID-19: A randomised, double-blind, placebo-controlled, multicentre trial","volume":"395","author":"Wang","year":"2020","journal-title":"Lancet"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Cavalcanti, A.B., Zampieri, F.G., Rosa, R.G., Azevedo, L.C.P., Veiga, V.C., Avezum, A., Damiani, L.P., Marcadenti, A., Kawano-Dourado, L., and Lisboa, T. (2020). Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19. N. Engl. J. Med., 1\u201312.","DOI":"10.1056\/NEJMoa2019014"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1016\/j.biotechadv.2015.08.001","article-title":"Discovery and resupply of pharmacologically active plant-derived natural products: A review","volume":"33","author":"Atanasov","year":"2015","journal-title":"Biotechnol. Adv."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e125124","DOI":"10.1016\/j.foodchem.2019.125124","article-title":"Anti-inflammatory effects of flavonoids","volume":"299","author":"Maleki","year":"2019","journal-title":"Food Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.canlet.2015.07.004","article-title":"Polyphenols as mitochondria-targeted anticancer drugs","volume":"366","author":"Gorlach","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3540","DOI":"10.3390\/ijms14023540","article-title":"Flavonoids as antioxidants and developmental regulators: Relative significance in plants and humans","volume":"14","author":"Brunetti","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.neuint.2015.09.006","article-title":"Neuroprotective effects of chrysin: From chemistry to medicine","volume":"90","author":"Nabavi","year":"2015","journal-title":"Neurochem. Int."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.2174\/1381612825666190702095612","article-title":"Essential oil and ethanol extract of oregano (Origanum vulgare L.) from Armenian flora as a natural source of terpenes, flavonoids and other phytochemicals with antiradical, antioxidant, metal chelating, tyrosinase inhibitory and antibacterial activity","volume":"25","author":"Moghrovyan","year":"2019","journal-title":"Curr. Pharm. Des."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"132","DOI":"10.2174\/0929867321666140916113443","article-title":"Antibacterial activities of flavonoids: Structure-activity relationship and mechanism","volume":"22","author":"Xie","year":"2015","journal-title":"Curr. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1002\/jmv.1890150110","article-title":"Antiviral effect of flavonoids on human viruses","volume":"15","author":"Kaul","year":"1985","journal-title":"J. Med. Virol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1080\/01652176.2020.1727993","article-title":"Emerging novel coronavirus (2019-nCoV)\u2014Current scenario, evolutionary perspective based on genome analysis and recent developments","volume":"40","author":"Malik","year":"2020","journal-title":"Vet. Q."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1678","DOI":"10.7150\/ijbs.45053","article-title":"SARS-CoV-2: An emerging coronavirus that causes a global threat","volume":"16","author":"Zheng","year":"2020","journal-title":"Int. J. Biol. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Banerjee, A., Kulcsar, K., Misra, V., Frieman, M., and Mossman, K. (2019). Bats and coronaviruses. Viruses, 11.","DOI":"10.3389\/fimmu.2020.00026"},{"key":"ref_40","first-page":"1","article-title":"Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic","volume":"38","author":"Prompetchara","year":"2020","journal-title":"Asian Pac. J. Allergy Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/s12985-020-01369-z","article-title":"SARS-CoV-2: Characteristics and current advances in research","volume":"17","author":"Yang","year":"2020","journal-title":"Virol. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5025","DOI":"10.1073\/pnas.97.10.5025","article-title":"The making of infectious viral RNA: No size limit in sight","volume":"97","author":"Lai","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"vey035","DOI":"10.1093\/ve\/vey035","article-title":"Identification and characterization of Coronaviridae genomes from Vietnamese bats and rats based on conserved protein domains","volume":"4","author":"Phan","year":"2018","journal-title":"Virus Evol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/s41586-020-2223-y","article-title":"Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors","volume":"582","author":"Jin","year":"2020","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1007\/s10096-020-03899-4","article-title":"The genetic sequence, origin, and diagnosis of SARS-CoV-2","volume":"39","author":"Wang","year":"2020","journal-title":"Eur. J. Clin. Microbio. Infect. Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1080\/22221751.2020.1719902","article-title":"Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan","volume":"9","author":"Chan","year":"2020","journal-title":"Emerg. Microbes Infect."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41586-020-2012-7","article-title":"A pneumonia outbreak associated with a new coronavirus of probable bat origin","volume":"579","author":"Zhou","year":"2020","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"100672","DOI":"10.1016\/j.nmni.2020.100672","article-title":"Epidemiology, genome, and clinical features of the pandemic SARS-CoV-2: A recent view","volume":"35","author":"Abduljalil","year":"2020","journal-title":"New Microbes New Infect."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Decaro, N., and Lorusso, A. (2020). Novel human coronavirus (SARS-CoV-2): A lesson from animal coronaviruses. Vet. Microb., 108693.","DOI":"10.1016\/j.vetmic.2020.108693"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"14614","DOI":"10.1128\/JVI.79.23.14614-14621.2005","article-title":"ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia","volume":"79","author":"Jia","year":"2005","journal-title":"J. Virol."},{"key":"ref_51","first-page":"1","article-title":"Simulation of the clinical and pathological manifestations of Coronavirus Disease 2019 (COVID-19) in golden Syrian hamster model: Implications for disease pathogenesis and transmissibility","volume":"325","author":"Chan","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1001\/jamacardio.2020.1282","article-title":"Coronavirus Disease 2019 (COVID-19) Infection and Renin Angiotensin System Blockers","volume":"5","author":"Bavishi","year":"2020","journal-title":"JAMA Cardiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"F600","DOI":"10.1152\/ajprenal.00600.2012","article-title":"Regulation of urinary ACE2 in diabetic mice","volume":"305","author":"Wysocki","year":"2013","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Xiao, F., Hiremath, S., Knoll, G., Zimpelmann, J., Srivaratharajah, K., Jadhav, D., Fergusson, D., Kennedy, C.R., and Burns, K.D. (2012). Increased urinary angiotensin-converting enzyme 2 in renal transplant patients with diabetes. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0037649"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"226","DOI":"10.4103\/CJP.CJP_57_19","article-title":"Lifetime overproduction of circulating angiotensin-(1-7) in rats attenuates the increase in skeletal muscle damage biomarkers after exhaustive exercise","volume":"62","author":"Becker","year":"2019","journal-title":"Chin. J. Physiol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Zeinalian, M., Salari-Jazi, A., Jannesari, A., and Khanahmad, H. (2020). A potential protective role of losartan against coronavirus-induced lung damage. Infect. Control Hosp. Epidemiol., 1\u20132.","DOI":"10.1017\/ice.2020.80"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/S2468-1253(20)30048-0","article-title":"Enteric involvement of coronaviruses: Is faecal\u2013oral transmission of SARS-CoV-2 possible?","volume":"5","author":"Yeo","year":"2020","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Chen, R., Yu, J., Wang, K., Chen, Z., Wen, C., and Xu, Z. (2020). The spatial and cell-type distribution of SARS-CoV-2 receptor ACE2 in human and mouse brain. BioRxiv, 1\u201326.","DOI":"10.1101\/2020.04.07.030650"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor","volume":"182","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1113\/expphysiol.2007.040048","article-title":"The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice","volume":"93","author":"Imai","year":"2008","journal-title":"Exp. Physiol."},{"key":"ref_61","first-page":"702","article-title":"In silico study of the spike protein from SARS-CoV-2 interaction with ACE2: Similarity with SARS-CoV, hot-spot analysis and effect of the receptor polymorphism","volume":"527","author":"Othman","year":"2020","journal-title":"BioRxiv"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"49414","DOI":"10.1074\/jbc.M408782200","article-title":"Crystal structure of severe acute respiratory syndrome coronavirus spike protein fusion core","volume":"279","author":"Xu","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1038\/s41423-020-0374-2","article-title":"Fusion mechanism of 2019-nCoV and fusion inhibitors targeting HR1 domain in spike protein","volume":"17","author":"Xia","year":"2020","journal-title":"Cell Mol. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"5071","DOI":"10.1016\/j.vaccine.2020.04.070","article-title":"The biological characteristics of SARS-CoV-2 Spike protein Pro330-Leu650","volume":"38","author":"Su","year":"2020","journal-title":"Vaccine"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/s41586-020-2179-y","article-title":"Structural basis of receptor recognition by SARS-CoV-2","volume":"581","author":"Shang","year":"2020","journal-title":"Nature"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Basu, A., Sarkar, A., and Maulik, U. (2020). Computational approach for the design of potential spike protein binding natural compounds in SARS-CoV2. OSF Preprints, 1\u201322.","DOI":"10.21203\/rs.3.rs-33181\/v1"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Xu, J., Zhao, S., Teng, T., Abdalla, A.E., Zhu, W., Xie, L., Wang, Y., and Guo, X. (2020). Systematic Comparison of Two Animal-to-Human Transmitted Human Coronaviruses: SARS-CoV-2 and SARS-CoV. Viruses, 12.","DOI":"10.3390\/v12020244"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"104859","DOI":"10.1016\/j.phrs.2020.104859","article-title":"Candidate drugs against SARS-CoV-2 and COVID-19","volume":"157","author":"McKee","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"807","DOI":"10.2174\/1871530320666200427112902","article-title":"Focus on Receptors for Coronaviruses with Special Reference to Angiotensin-converting Enzyme 2 as a Potential Drug Target\u2014A Perspective","volume":"20","author":"Magrone","year":"2020","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fcimb.2020.00317","article-title":"ACE2, Much More Than Just a Receptor for SARS-COV-2","volume":"10","author":"Samavati","year":"2020","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.virol.2006.01.029","article-title":"Identification of critical determinants on ACE2 for SARS-CoV entry and development of a potent entry inhibitor","volume":"350","author":"Han","year":"2006","journal-title":"Virology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"104016","DOI":"10.1016\/j.jff.2020.104016","article-title":"Exploring the Active Compounds of Traditional Mongolian Medicine in Intervention of Novel Coronavirus (COVID-19) Based on Molecular Docking Method","volume":"71","author":"Yu","year":"2020","journal-title":"J. Func. Foods"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1128\/JVI.00831-20","article-title":"Comparison of SARS-CoV-2 spike protein binding to ACE2 receptors from human, pets, farm animals, and putative intermediate hosts","volume":"94","author":"Zhai","year":"2020","journal-title":"J. Virol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"13185","DOI":"10.1021\/bi035268s","article-title":"Angiotensin-converting enzyme-2 (ACE2): Comparative modeling of the active site, specificity requirements, and chloride dependence","volume":"42","author":"Guy","year":"2003","journal-title":"Biochemistry"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1093\/eurheartj\/ehaa235","article-title":"SARS-CoV2: Should inhibitors of the renin\u2013angiotensin system be withdrawn in patients with COVID-19?","volume":"41","author":"Kuster","year":"2020","journal-title":"Eur. Heart J."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1161\/CIRCRESAHA.120.317134","article-title":"Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19","volume":"126","author":"Zhang","year":"2020","journal-title":"Circ. Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1080\/08038020802144383","article-title":"The safety profile of telmisartan as monotherapy or combined with hydrochlorothiazide: A retrospective analysis of 50 studies","volume":"17","author":"Schumacher","year":"2008","journal-title":"Blood Press."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Rothlin, R.P., Vetulli, H.M., Duarte, M., and Pelorosso, F.G. (2020). Telmisartan as tentative angiotensin receptor blocker therapeutic for COVID-19. Drug Dev. Res., 1\u20133.","DOI":"10.1002\/ddr.21679"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1038\/ajh.2010.51","article-title":"Inhibition of Angiotensin-Converting Enzyme 2 Exacerbates Cardiac Hypertrophy and Fibrosis in Ren-2 Hypertensive Rats","volume":"23","author":"Trask","year":"2010","journal-title":"Am. J. Hypert."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.ejphar.2016.01.007","article-title":"Angiotensin converting enzyme versus angiotensin converting enzyme-2 selectivity of MLN-4760 and DX600 in human and murine bone marrow-derived cells","volume":"774","author":"Joshi","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"17996","DOI":"10.1074\/jbc.M311191200","article-title":"ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis","volume":"279","author":"Towler","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.acvd.2013.01.004","article-title":"Effects of enalapril on the expression of cardiac angiotensin-converting enzyme and angiotensin-converting enzyme 2 in spontaneously hypertensive rats","volume":"106","author":"Yang","year":"2013","journal-title":"Arch. Cardiovasc. Dis."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1093\/ajh\/hps088","article-title":"Sex Differences in Angiotensin-Converting Enzyme Modulation of Ang (1\u20137) Levels in Normotensive WKY Rats","volume":"26","author":"Bhatia","year":"2013","journal-title":"Am. J. Hypertens."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1161\/HYPERTENSIONAHA.112.198622","article-title":"Murine recombinant angiotensin-converting enzyme 2: Effect on angiotensin II-dependent hypertension and distinctive angiotensin-converting enzyme 2 inhibitor characteristics on rodent and human angiotensin-converting enzyme 2","volume":"60","author":"Ye","year":"2012","journal-title":"Hypertension"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.antiviral.2009.12.001","article-title":"TACE antagonists blocking ACE2 shedding caused by the spike protein of SARS-CoV are candidate antiviral compounds","volume":"85","author":"Haga","year":"2010","journal-title":"Antivir. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/ajh\/hpu086","article-title":"Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by olmesartan, an angiotensin II receptor blocker","volume":"28","author":"Furuhashi","year":"2015","journal-title":"Am. J. Hypertens."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.lfs.2019.02.027","article-title":"Concurrent neprilysin inhibition and renin-angiotensin system modulations prevented diabetic nephropathy","volume":"221","author":"Malek","year":"2019","journal-title":"Life Sci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/1743-422X-2-69","article-title":"Chloroquine is a potent inhibitor of SARS coronavirus infection and spread","volume":"2","author":"Vincent","year":"2005","journal-title":"Virol. J."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3118","DOI":"10.1111\/bph.13946","article-title":"Diminazene aceturate prevents nephropathy by increasing glomerular ACE2 and AT2 receptor expression in a rat model of type1 diabetes","volume":"174","author":"Goru","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1161\/01.HYP.0000146120.29648.36","article-title":"Structure-Based Discovery of a Novel Angiotensin-Converting Enzyme 2 Inhibitor","volume":"44","author":"Huentelman","year":"2004","journal-title":"Hypertension"},{"key":"ref_91","first-page":"E014","article-title":"Inhibitors of RAS Might Be a Good Choice for the Therapy of COVID-19 Pneumonia","volume":"43","author":"Sun","year":"2020","journal-title":"Chin. J. Tuberc. Respir. Dis."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1016\/j.lfs.2005.09.038","article-title":"Age- and gender-related difference of ACE2 expression in rat lung","volume":"78","author":"Xie","year":"2006","journal-title":"Life Sci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1007\/s10295-006-0107-2","article-title":"Drug discovery from natural products","volume":"33","author":"Gullo","year":"2006","journal-title":"J. Ind. Microbiol. Biotechnol."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Thomford, N.E., Senthebane, D.A., Rowe, A., Munro, D., Seele, P., Maroyi, A., and Dzobo, K. (2018). Natural Products for Drug Discovery in the 21st Century: Innovations for Novel Drug Discovery. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19061578"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.apsb.2016.06.003","article-title":"The modification of natural products for medical use","volume":"7","author":"Guo","year":"2017","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1021\/acs.jnatprod.9b01285","article-title":"Natural Products as Sources of New Drugs over the Nearly Four Decades from 01\/1981 to 09\/2019","volume":"83","author":"Newman","year":"2020","journal-title":"J. Nat. Prod."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s13337-015-0276-6","article-title":"Herbal plants and plant preparations as remedial approach for viral diseases","volume":"26","author":"Ganjhu","year":"2015","journal-title":"Virusdisease"},{"key":"ref_98","first-page":"1","article-title":"Revealing the Potency of Citrus and Galangal Constituents to Halt SARS-CoV-2 Infection","volume":"214","author":"Utomo","year":"2020","journal-title":"Preprints"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1002\/ptr.2008","article-title":"Inhibition of angiotensin converting enzyme (ACE) by flavonoids isolated from Ailanthus excelsa (Roxb) (Simaroubaceae)","volume":"21","author":"Loizzo","year":"2007","journal-title":"Phytother. Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.antiviral.2006.04.014","article-title":"Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction","volume":"74","author":"Ho","year":"2007","journal-title":"Antivir. Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.jep.2009.09.059","article-title":"Inhibition of angiotensin convertin enzyme (ACE) activity by the anthocyanins delphinidin- and cyanidin-3-O-sambubiosides from Hibiscus sabdariffa","volume":"127","author":"Ojeda","year":"2010","journal-title":"J. Ethnopharmacol."},{"key":"ref_102","first-page":"693","article-title":"Effects of apigenin on the expression of angiotensin-converting enzyme 2 in kidney in spontaneously hypertensive rats","volume":"39","author":"Sui","year":"2010","journal-title":"J. Hyg. Res."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Guerrero, L., Castillo, J., Quinones, M., Garcia-Vallve, S., Arola, L., Pujadas, G., and Muguerza, B. (2012). Inhibition of angiotensin-converting enzyme activity by flavonoids: Structure-activity relationship studies. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0049493"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"219","DOI":"10.2220\/biomedres.36.219","article-title":"Nicotianamine is a novel angiotensin-converting enzyme 2 inhibitor in soybean","volume":"36","author":"Takahashi","year":"2015","journal-title":"Biomed. Res. (Tokyo Japan)"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Hettihewa, S.K., Hemar, Y., and Rupasinghe, H.P.V. (2018). Flavonoid-Rich Extract of Actinidia macrosperma (A Wild Kiwifruit) Inhibits Angiotensin-Converting Enzyme In Vitro. Foods, 7.","DOI":"10.3390\/foods7090146"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Joshi, R.S., Jagdale, S.S., Bansode, S.B., Shankar, S.S., Tellis, M.B., Pandya, V.K., Chugh, A., Giri, A.P., and Kulkarni, M.J. (2020). Discovery of Potential Multi-Target-Directed Ligands by Targeting Host-specific SARS-CoV-2 Structurally Conserved Main Protease($). J. Biomol. Struct. Dyn., 1\u201316.","DOI":"10.1080\/07391102.2020.1760137"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"401","DOI":"10.3109\/13880209.2011.608076","article-title":"Inhibitory activities of baicalin against renin and angiotensin-converting enzyme","volume":"50","author":"Deng","year":"2012","journal-title":"Pharm. Biol."},{"key":"ref_108","first-page":"1","article-title":"Potential natural compounds for preventing 2019-nCoV infection","volume":"358","author":"Chen","year":"2020","journal-title":"Preprints"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1017\/jns.2016.41","article-title":"Flavonoids: An overview","volume":"5","author":"Panche","year":"2016","journal-title":"J. Nutr. Sci."},{"key":"ref_110","unstructured":"Durairaj, R.B. (2005). Resorcinol Structure and Physical Properties. Resorcinol. Chem. Technol. Appl., 1\u20139."},{"key":"ref_111","first-page":"1","article-title":"Evaluation of Flavonoids as 2019-nCoV Cell Entry Inhibitor Through Molecular Docking and Pharmacological Analysis","volume":"6","author":"Bhowmik","year":"2020","journal-title":"ChemRxiv"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"4049","DOI":"10.1016\/j.bmcl.2012.04.081","article-title":"Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13","volume":"22","author":"Yu","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1055\/s-0033-1360277","article-title":"Kaempferol derivatives as antiviral drugs against the 3a channel protein of coronavirus","volume":"80","author":"Schwarz","year":"2014","journal-title":"Planta Med."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"11334","DOI":"10.1128\/JVI.78.20.11334-11339.2004","article-title":"Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells","volume":"78","author":"Yi","year":"2004","journal-title":"J. Virol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1007\/s10529-011-0845-8","article-title":"Flavonoid-mediated inhibition of SARS coronavirus 3C-like protease expressed in Pichia pastoris","volume":"34","author":"Nguyen","year":"2012","journal-title":"Biotechnol. Lett."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1111\/cbdd.13604","article-title":"Characteristics of flavonoids as potent MERS-CoV 3C-like protease inhibitors","volume":"94","author":"Jo","year":"2019","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1080\/14756366.2016.1265519","article-title":"Evaluation of polyphenols from Broussonetia papyrifera as coronavirus protease inhibitors","volume":"32","author":"Park","year":"2017","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Wu, C., Liu, Y., Yang, Y., Zhang, P., Zhong, W., Wang, Y., Wang, Q., Xu, Y., Li, M., and Li, X. (2020). Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm. Sin. B.","DOI":"10.1016\/j.apsb.2020.02.008"},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Dai, W., Bi, J., Li, F., Wang, S., Huang, X., Meng, X., Sun, B., Wang, D., Kong, W., and Jiang, C. (2019). Antiviral Efficacy of Flavonoids against Enterovirus 71 Infection in Vitro and in Newborn Mice. Viruses, 11.","DOI":"10.3390\/v11070625"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"2539","DOI":"10.1007\/s00705-017-3417-y","article-title":"Flavonoids: Promising natural compounds against viral infections","volume":"162","author":"Zakaryan","year":"2017","journal-title":"Arch. Virol."},{"key":"ref_121","unstructured":"Cheng, L., Zheng, W., Li, M., Huang, J., Bao, S., Xu, Q., and Ma, Z. (2020). Citrus fruits are rich in flavonoids for immunoregulation and potential targeting ACE2. Preprints, 2020020313."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.4049\/jimmunol.1701686","article-title":"Glutathione Reductase Promotes Fungal Clearance and Suppresses Inflammation during Systemic Candida albicans Infection in Mice","volume":"203","author":"Kim","year":"2019","journal-title":"J. Immunol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1021\/acs.jnatprod.5b01055","article-title":"Natural products as sources of new drugs from 1981 to 2014","volume":"79","author":"Newman","year":"2016","journal-title":"J. Nat. Prod."},{"key":"ref_124","unstructured":"Brewster, R.M., and Manthey, J.A. (2015). Flavonoid Compositions and Uses Thereof. (WO2015152648A1), Google Patents."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ajps.2017.08.004","article-title":"Bioactive flavonoids in medicinal plants: Structure, activity and biological fate","volume":"13","author":"Wang","year":"2018","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Muchtaridi, M., Sugijanto, M., Mohd Gazzali, A., and Wahab, H.A. (2020). Anti-Neuraminidase Bioactives from Manggis Hutan (Garcinia celebica L.) Leaves: Partial Purification and Molecular Characterization. Molecules, 25.","DOI":"10.3390\/molecules25040821"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"162750","DOI":"10.1155\/2013\/162750","article-title":"Chemistry and Biological Activities of Flavonoids: An Overview","volume":"2013","author":"Kumar","year":"2013","journal-title":"Sci. World J."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Parnham, M. (2015). Flavonoids as Anti-inflammatory Agents. Encyclopedia of Inflammatory Diseases, Springer.","DOI":"10.1007\/978-3-0348-0620-6"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1111\/1541-4337.12204","article-title":"Flavonoids as Potent Scavengers of Hydroxyl Radicals","volume":"15","author":"Treml","year":"2016","journal-title":"Compr. Rev. Food Sci. Food Saf."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1093\/ajcn\/74.4.418","article-title":"Flavonoids: A review of probable mechanisms of action and potential applications","volume":"74","author":"Nijveldt","year":"2001","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"199","DOI":"10.3103\/S009639251804003X","article-title":"Role of Reactive Oxygen Species in Inflammation: A Minireview","volume":"73","author":"Chelombitko","year":"2018","journal-title":"Mosc. Univ. Biol. Sci. Bull."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.3389\/fphar.2018.01162","article-title":"Antioxidant and Oxidative Stress: A Mutual Interplay in Age-Related Diseases","volume":"9","author":"Tan","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"91","DOI":"10.15406\/ppij.2020.08.00285","article-title":"Flavonoids: A vital resource in healthcare and medicine","volume":"8","author":"Mondal","year":"2020","journal-title":"Pharm. Pharmacol. Int. J."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.theochem.2007.05.036","article-title":"Theoretical affinity order among flavonoids and amino acid residues: An approach to understand flavonoid\u2013protein interactions","volume":"819","year":"2007","journal-title":"J. Mol. Struct. THEOCHEM"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"256294","DOI":"10.1155\/2012\/256294","article-title":"Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease","volume":"2012","author":"Tikellis","year":"2012","journal-title":"Int. J. Pept."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/17\/3980\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:05:27Z","timestamp":1760177127000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/17\/3980"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,1]]},"references-count":135,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["molecules25173980"],"URL":"https:\/\/doi.org\/10.3390\/molecules25173980","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,1]]}}}