Bioactive Polyphenolic Compounds Showing Strong Antiviral Activities against Severe Acute Respiratory Syndrome Coronavirus 2
Ahmed Kandeil, Ahmed Mostafa, Omnia Kutkat, Yassmin Moatasim, Ahmed A Al-Karmalawy, Adel A Rashad, Ahmed E Kayed, Azza E Kayed, Rabeh El-Shesheny, Ghazi Kayali, Mohamed A Ali
Pathogens, doi:10.3390/pathogens10060758
Until now, there has been no direct evidence of the effectiveness of repurposed FDAapproved drugs against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections. Although curcumin, hesperidin, and quercetin have broad spectra of pharmacological properties, their antiviral activities against SARS-CoV-2 remain unclear. Our study aimed to assess the in vitro antiviral activities of curcumin, hesperidin, and quercetin against SARS-CoV-2 compared to hydroxychloroquine and determine their mode of action. In Vero E6 cells, these compounds significantly inhibited virus replication, mainly as virucidal agents primarily indicating their potential activity at the early stage of viral infection. To investigate the mechanism of action of the tested compounds, molecular docking studies were carried out against both SARS-CoV-2 spike (S) and main protease (Mpro) receptors. Collectively, the obtained in silico and in vitro findings suggest that the compounds could be promising SARS-CoV-2 Mpro inhibitors. We recommend further preclinical and clinical studies on the studied compounds to find a potential therapeutic targeting COVID-19 in the near future.
Data Availability Statement: The data presented in this study are available within the article and Supplementary Materials.
Conflicts of Interest: The authors declare no conflict of interest.
References
Abouaitah, Swiderska-Sroda, Kandeil, Salman, Wojnarowicz et al., Virucidal Action Against Avian Influenza H5N1 Virus and Immunomodulatory Effects of Nanoformulations Consisting of Mesoporous Silica Nanoparticles Loaded with Natural Prodrugs, Int. J. Nanomed,
doi:10.2147/IJN.S247692Al-Karmalawy, Dahab, Metwaly, Elhady, Elkaeed et al., Molecular Docking and Dynamics Simulation Revealed the Potential Inhibitory Activity of ACEIs Against SARS-CoV-2 Targeting the hACE2 Receptor, Front. Chem,
doi:10.3389/fchem.2021.661230Al-Karmalawy, Eissa, Molecular docking and dynamics simulations reveal the potential of anti-HCV drugs to inhibit COVID-19 main protease, Pharm. Sci,
doi:10.34172/PS.2021.3Al-Karmalawy, Khattab, Molecular modelling of mebendazole polymorphs as a potential colchicine binding site inhibitor, New J. Chem,
doi:10.1039/D0NJ02844DAlnajjar, Mostafa, Kandeil, Al-Karmalawy, Molecular docking, molecular dynamics, and in vitro studies reveal the potential of angiotensin II receptor blockers to inhibit the COVID-19 main protease, Heliyon,
doi:10.1016/j.heliyon.2020.e05641Annunziata, Zamparelli, Santoro, Ciampaglia, Stornaiuolo et al., May Polyphenols Have a Role Against Coronavirus Infection? An Overview of in vitro Evidence, Front. Med,
doi:10.3389/fmed.2020.00240Choi, Song, Park, Kwon, Inhibitory effects of quercetin 3-rhamnoside on influenza A virus replication, Eur. J. Pharm. Sci,
doi:10.1016/j.ejps.2009.03.002Chu, Pan, Cheng, Hui, Krishnan et al., Molecular Diagnosis of a Novel Coronavirus (2019-nCoV) Causing an Outbreak of Pneumonia, Clin. Chem,
doi:10.1093/clinchem/hvaa029Colpitts, Schang, Rachmawati, Frentzen, Pfaender et al., Turmeric curcumin inhibits entry of all hepatitis C virus genotypes into human liver cells, Gut
Dong, Wei, Zhang, Hao, Huang et al., A dual character of flavonoids in influenza A virus replication and spread through modulating cell-autonomous immunity by MAPK signaling pathways, Sci. Rep,
doi:10.1038/srep07237El Shal, Eid, El-Sayed, El-Sayed, Al-Karmalawy, Concanavalin-A shows synergistic cytotoxicity with tamoxifen via inducing apoptosis in estrogen receptor-positive breast cancer: In vitro and molecular docking studies, Pharm. Sci,
doi:10.34172/PS.2021.22Eliaa, Al-Karmalawy, Saleh, Elshal, Empagliflozin and Doxorubicin Synergistically Inhibit the Survival of Triple-Negative Breast Cancer Cells via Interfering with the mTOR Pathway and Inhibition of Calmodulin: In Vitro and Molecular Docking Studies, ACS Pharmacol. Transl. Sci,
doi:10.1021/acsptsci.0c00144Elmaaty, Alnajjar, Hamed, Khattab, Khalifa et al., Revisiting activity of some glucocorticoids as a potential inhibitor of SARS-CoV-2 main protease: Theoretical study, RSC Adv,
doi:10.1039/D0RA10674GElmaaty, Darwish, Khattab, Elhady, Salah et al., In a search for potential drug candidates for combating COVID-19: Computational study revealed salvianolic acid B as a potential therapeutic targeting 3CLpro and spike proteins, J. Biomol. Struct. Dyn,
doi:10.1080/07391102.2021.1918256Gao, Wang, Wei, Men, Zheng et al., Anticancer effect and mechanism of polymer micelle-encapsulated quercetin on ovarian cancer, Nanoscale,
doi:10.1039/c2nr32181eGhanem, Emara, Muawia, El Maksoud, Al-Karmalawy et al., Tanshinone IIA synergistically enhances the antitumor activity of doxorubicin by interfering with the PI3K/AKT/mTOR pathway and inhibition of topoisomerase II: In vitro and molecular docking studies, New J. Chem,
doi:10.1039/D0NJ04088FHaggag, El-Ashmawy, Okasha, Is hesperidin essential for prophylaxis and treatment of COVID-19 Infection?, Med. Hypotheses,
doi:10.1016/j.mehy.2020.109957Hajialyani, Farzaei, Echeverría, Nabavi, Uriarte et al., Hesperidin as a Neuroprotective Agent: A Review of Animal and Clinical Evidence, Molecules,
doi:10.3390/molecules24030648Harwood, Danielewska-Nikiel, Borzelleca, Flamm, Williams et al., A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties, Food Chem. Toxicol,
doi:10.1016/j.fct.2007.05.015Johari, Kianmehr, Mustafa, Abubakar, Zandi, Antiviral activity of baicalein and quercetin against the Japanese encephalitis virus, Int. J. Mol. Sci,
doi:10.3390/ijms131216785Khattab, Al-Karmalawy, Revisiting Activity of Some Nocodazole Analogues as a Potential Anticancer Drugs Using Molecular Docking and DFT Calculations, Front. Chem,
doi:10.3389/fchem.2021.628398Kobayashi, Tanabe, Sugiyama, Konishi, Transepithelial transport of hesperetin and hesperidin in intestinal Caco-2 cell monolayers, Biochim. Biophys. Acta (BBA) Biomembr,
doi:10.1016/j.bbamem.2007.08.020Kuo, Lin, Tsai, Chou, Kung et al., Samarangenin B from Limonium sinense Suppresses Herpes Simplex Virus Type 1 Replication in Vero Cells by Regulation of Viral Macromolecular Synthesis, Antimicrob. Agents Chemother,
doi:10.1128/AAC.46.9.2854-2864.2002Mazumder, Raghavan, Weinstein, Kohn, Pommier, Inhibition of human immunodeficiency virus type-1 integrase by curcumin, Biochem. Pharmacol,
doi:10.1016/0006-2952(95)98514-AMoghadamtousi, Kadir, Hassandarvish, Tajik, Abubakar et al., A Review on Antibacterial, Antiviral, and Antifungal Activity of Curcumin, BioMed Res. Int,
doi:10.1155/2014/186864Mosmann, Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays, J. Immunol. Methods,
doi:10.1016/0022-1759(83)90303-4Mostafa, Kandeil, Elshaier, Kutkat, Moatasim et al., FDA-Approved Drugs with Potent In Vitro Antiviral Activity against Severe Acute Respiratory Syndrome Coronavirus 2, Pharmaceuticals,
doi:10.3390/ph13120443Nabila, Suada, Denis, Yohan, Adi et al., Antiviral Action of Curcumin Encapsulated in Nanoemulsion against Four Serotypes of Dengue Virus, Pharm. Nanotechnol,
doi:10.2174/2211738507666191210163408Orfali, Rateb, Hassan, Alonazi, Gomaa et al., Sinapic Acid Suppresses SARS CoV-2 Replication by Targeting Its Envelope Protein, Antibiotics,
doi:10.3390/antibiotics10040420Parvez, Rehman, Alam, Al-Dosari, Alqasoumi et al., Plant-derived antiviral drugs as novel hepatitis B virus inhibitors: Cell culture and molecular docking study, Saudi Pharm. J,
doi:10.1016/j.jsps.2018.12.008Rojas, Del Campo, Clement, Lemasson, García-Valdecasas et al., Effect of Quercetin on Hepatitis C Virus Life Cycle: From Viral to Host Targets, Sci. Rep,
doi:10.1038/srep31777Roshdy, Rashed, Kandeil, Mostafa, Moatasim et al., EGYVIR: An immunomodulatory herbal extract with potent antiviral activity against SARS-CoV-2, PLoS ONE,
doi:10.1371/journal.pone.0241739Samra, Soliman, Zaki, Ashour, Al-Karmalawy et al., Bioassay-guided isolation of a new cytotoxic ceramide from Cyperus rotundus L, S. Afr. J. Bot,
doi:10.1016/j.sajb.2021.02.007Sarhan, Ashour, Al-Karmalawy, The journey of antimalarial drugs against SARS-CoV-2: Review article, Inform. Med. Unlocked,
doi:10.1016/j.imu.2021.100604Schuhmacher, Reichling, Schnitzler, Virucidal effect of peppermint oil on the enveloped viruses herpes simplex virus type 1 and type 2 in vitro, Phytomedicine,
doi:10.1078/094471103322331467Soltane, Chrouda, Mostafa, Al-Karmalawy, Chouaïb et al., Strong Inhibitory Activity and Action Modes of Synthetic Maslinic Acid Derivative on Highly Pathogenic Coronaviruses: COVID-19 Drug Candidate, Pathogens,
doi:10.3390/pathogens10050623Swatson, Katoh-Kurasawa, Shaulsky, Alexander, Curcumin affects gene expression and reactive oxygen species via a PKA dependent mechanism in Dictyostelium discoideum, PLoS ONE,
doi:10.1371/journal.pone.0187562Vázquez-Calvo, De Oya, Martín-Acebes, Garcia-Moruno, Saiz, Antiviral Properties of the Natural Polyphenols Delphinidin and Epigallocatechin Gallate against the Flaviviruses West Nile Virus, Zika Virus, and Dengue Virus, Front. Microbiol,
doi:10.3389/fmicb.2017.01314Wu, Hou, Cao, Zuo, Xue et al., Virucidal efficacy of treatment with photodynamically activated curcumin on murine norovirus bio-accumulated in oysters, Photodiagn. Photodyn. Ther,
doi:10.1016/j.pdpdt.2015.06.005Wu, Li, Li, He, Jiang et al., Quercetin as an Antiviral Agent Inhibits Influenza A Virus (IAV) Entry, Viruses,
doi:10.3390/v8010006Wu, Liu, Yang, Zhang, Zhong et al., 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.2020.02.008Yang, Li, Li, Wang, Huang, Synergistic antiviral effect of curcumin functionalized graphene oxide against respiratory syncytial virus infection, Nanoscale,
doi:10.1039/C7NR06520EZaki, Al-Karmalawy, El-Amier, Ashour, Molecular docking reveals the potential of Cleome amblyocarpa isolated compounds to inhibit COVID-19 virus main protease, New J. Chem,
doi:10.1039/D0NJ03611KZaki, Ashour, Elhady, Darwish, Al-Karmalawy, Calendulaglycoside A Showing Potential Activity Against SARS-CoV-2 Main Protease: Molecular Docking, Molecular Dynamics, and SAR Studies, J. Tradit. Complement. Med
Zhang, Zhan, Yao, Gao, Shong, Antiviral activity of tannin from the pericarp of Punica granatum L. against genital Herpes virus in vitro, China J. Chin. Mater. Med
{ 'indexed': {'date-parts': [[2022, 4, 21]], 'date-time': '2022-04-21T11:06:14Z', 'timestamp': 1650539174233},
'reference-count': 59,
'publisher': 'MDPI AG',
'issue': '6',
'license': [ { 'start': { 'date-parts': [[2021, 6, 15]],
'date-time': '2021-06-15T00:00:00Z',
'timestamp': 1623715200000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0/'}],
'funder': [ {'name': 'Egyptian Academy of Scientific Research & Technology', 'award': ['project ID: 7303']},
{ 'DOI': '10.13039/100000060',
'name': 'National Institute of Allergy and Infectious Diseases',
'doi-asserted-by': 'publisher',
'award': ['HHSN272201400006C']}],
'content-domain': {'domain': [], 'crossmark-restriction': False},
'short-container-title': ['Pathogens'],
'abstract': '<jats:p>Until now, there has been no direct evidence of the effectiveness of repurposed '
'FDA-approved drugs against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) '
'infections. Although curcumin, hesperidin, and quercetin have broad spectra of '
'pharmacological properties, their antiviral activities against SARS-CoV-2 remain unclear. Our '
'study aimed to assess the in vitro antiviral activities of curcumin, hesperidin, and '
'quercetin against SARS-CoV-2 compared to hydroxychloroquine and determine their mode of '
'action. In Vero E6 cells, these compounds significantly inhibited virus replication, mainly '
'as virucidal agents primarily indicating their potential activity at the early stage of viral '
'infection. To investigate the mechanism of action of the tested compounds, molecular docking '
'studies were carried out against both SARS-CoV-2 spike (S) and main protease (Mpro) '
'receptors. Collectively, the obtained in silico and in vitro findings suggest that the '
'compounds could be promising SARS-CoV-2 Mpro inhibitors. We recommend further preclinical and '
'clinical studies on the studied compounds to find a potential therapeutic targeting COVID-19 '
'in the near future.</jats:p>',
'DOI': '10.3390/pathogens10060758',
'type': 'journal-article',
'created': {'date-parts': [[2021, 6, 16]], 'date-time': '2021-06-16T01:24:29Z', 'timestamp': 1623806669000},
'page': '758',
'source': 'Crossref',
'is-referenced-by-count': 30,
'title': [ 'Bioactive Polyphenolic Compounds Showing Strong Antiviral Activities against Severe Acute '
'Respiratory Syndrome Coronavirus 2'],
'prefix': '10.3390',
'volume': '10',
'author': [ { 'ORCID': 'http://orcid.org/0000-0003-3253-6961',
'authenticated-orcid': False,
'given': 'Ahmed',
'family': 'Kandeil',
'sequence': 'first',
'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-2878-5714',
'authenticated-orcid': False,
'given': 'Ahmed',
'family': 'Mostafa',
'sequence': 'additional',
'affiliation': []},
{'given': 'Omnia', 'family': 'Kutkat', 'sequence': 'additional', 'affiliation': []},
{'given': 'Yassmin', 'family': 'Moatasim', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-8173-6073',
'authenticated-orcid': False,
'given': 'Ahmed A.',
'family': 'Al-Karmalawy',
'sequence': 'additional',
'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0001-6113-0333',
'authenticated-orcid': False,
'given': 'Adel A.',
'family': 'Rashad',
'sequence': 'additional',
'affiliation': []},
{'given': 'Ahmed E.', 'family': 'Kayed', 'sequence': 'additional', 'affiliation': []},
{'given': 'Azza E.', 'family': 'Kayed', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-8798-2240',
'authenticated-orcid': False,
'given': 'Rabeh',
'family': 'El-Shesheny',
'sequence': 'additional',
'affiliation': []},
{'given': 'Ghazi', 'family': 'Kayali', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0002-5615-3212',
'authenticated-orcid': False,
'given': 'Mohamed A.',
'family': 'Ali',
'sequence': 'additional',
'affiliation': []}],
'member': '1968',
'published-online': {'date-parts': [[2021, 6, 15]]},
'reference': [ { 'key': 'ref1',
'unstructured': 'World Health Organization COVID-19 Dashboardhttps://covid19.who.int/'},
{'key': 'ref2', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.pone.0241739'},
{'key': 'ref3', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/antibiotics10040420'},
{'key': 'ref4', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/ph13120443'},
{'key': 'ref5', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.heliyon.2020.e05641'},
{'key': 'ref6', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.biotechadv.2014.04.004'},
{'key': 'ref7', 'doi-asserted-by': 'publisher', 'DOI': '10.1155/2014/186864'},
{'key': 'ref8', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.lfs.2005.12.007'},
{'key': 'ref9', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.pdpdt.2015.06.005'},
{'key': 'ref10', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/molecules21101401'},
{'key': 'ref11', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.pone.0187562'},
{'key': 'ref12', 'doi-asserted-by': 'publisher', 'DOI': '10.1039/C7NR06520E'},
{'key': 'ref13', 'doi-asserted-by': 'publisher', 'DOI': '10.2174/2211738507666191210163408'},
{'key': 'ref14', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.fct.2007.05.015'},
{'key': 'ref15', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.cellbi.2007.04.009'},
{'key': 'ref16', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s12272-001-1206-5'},
{'key': 'ref17', 'doi-asserted-by': 'publisher', 'DOI': '10.1039/c2nr32181e'},
{'key': 'ref18', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/ijms131216785'},
{'key': 'ref19', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/molecules25102379'},
{'key': 'ref20', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ejps.2009.03.002'},
{'key': 'ref21', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/v8010006'},
{'key': 'ref22', 'doi-asserted-by': 'publisher', 'DOI': '10.2147/IJN.S247692'},
{'key': 'ref23', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/molecules24030648'},
{'key': 'ref24', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/srep07237'},
{'key': 'ref25', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/molecules24173061'},
{'key': 'ref26', 'doi-asserted-by': 'publisher', 'DOI': '10.3389/fchem.2021.628398'},
{'key': 'ref27', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s12551-013-0130-2'},
{'key': 'ref28', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.imu.2021.100604'},
{'key': 'ref29', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.mehy.2020.109957'},
{'key': 'ref30', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.apsb.2020.02.008'},
{'key': 'ref31', 'doi-asserted-by': 'publisher', 'DOI': '10.34172/PS.2021.3'},
{'key': 'ref32', 'doi-asserted-by': 'publisher', 'DOI': '10.1039/D0NJ03611K'},
{'key': 'ref33', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.jtcme.2021.05.001'},
{'key': 'ref34', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/pathogens10050623'},
{'key': 'ref35', 'doi-asserted-by': 'publisher', 'DOI': '10.1080/07391102.2021.1918256'},
{'key': 'ref36', 'doi-asserted-by': 'publisher', 'DOI': '10.1039/D0RA10674G'},
{'key': 'ref37', 'doi-asserted-by': 'publisher', 'DOI': '10.3389/fchem.2021.661230'},
{'key': 'ref38', 'doi-asserted-by': 'publisher', 'DOI': '10.3389/fmicb.2017.01314'},
{'key': 'ref39', 'doi-asserted-by': 'publisher', 'DOI': '10.3389/fmed.2020.00240'},
{ 'key': 'ref40',
'doi-asserted-by': 'crossref',
'first-page': '1137',
'DOI': '10.1136/gutjnl-2012-304299',
'article-title': 'Turmeric curcumin inhibits entry of all hepatitis C virus genotypes '
'into human liver cells',
'volume': '63',
'author': 'Colpitts',
'year': '2014',
'journal-title': 'Gut'},
{'key': 'ref41', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.antiviral.2017.03.014'},
{'key': 'ref42', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/0006-2952(95)98514-A'},
{'key': 'ref43', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.pone.0062482'},
{'key': 'ref44', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.bbamem.2007.08.020'},
{'key': 'ref45', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.jsps.2018.12.008'},
{'key': 'ref46', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/srep31777'},
{'key': 'ref47', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/0022-1759(83)90303-4'},
{'key': 'ref48', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/clinchem/hvaa029'},
{ 'key': 'ref49',
'first-page': '556',
'article-title': 'Antiviral activity of tannin from the pericarp of Punica granatum L. '
'against genital Herpes virus in vitro',
'volume': '20',
'author': 'Zhang',
'year': '1995',
'journal-title': 'China J. Chin. Mater. Med.'},
{'key': 'ref50', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/AAC.46.9.2854-2864.2002'},
{'key': 'ref51', 'doi-asserted-by': 'publisher', 'DOI': '10.1078/094471103322331467'},
{ 'key': 'ref52',
'series-title': 'Molecular Operating Environment (MOE), 2008.10',
'year': '2016'},
{'key': 'ref53', 'doi-asserted-by': 'publisher', 'DOI': '10.1039/D0NJ02844D'},
{'key': 'ref54', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41586-020-2223-y'},
{'key': 'ref55', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41586-020-2179-y'},
{'key': 'ref56', 'doi-asserted-by': 'publisher', 'DOI': '10.34172/PS.2021.22'},
{'key': 'ref57', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.sajb.2021.02.007'},
{'key': 'ref58', 'doi-asserted-by': 'publisher', 'DOI': '10.1021/acsptsci.0c00144'},
{'key': 'ref59', 'doi-asserted-by': 'publisher', 'DOI': '10.1039/D0NJ04088F'}],
'container-title': ['Pathogens'],
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://www.mdpi.com/2076-0817/10/6/758/pdf',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2021, 6, 17]],
'date-time': '2021-06-17T16:17:41Z',
'timestamp': 1623946661000},
'score': 1,
'resource': {'primary': {'URL': 'https://www.mdpi.com/2076-0817/10/6/758'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2021, 6, 15]]},
'references-count': 59,
'journal-issue': {'issue': '6', 'published-online': {'date-parts': [[2021, 6]]}},
'alternative-id': ['pathogens10060758'],
'URL': 'http://dx.doi.org/10.3390/pathogens10060758',
'relation': {},
'ISSN': ['2076-0817'],
'issn-type': [{'value': '2076-0817', 'type': 'electronic'}],
'subject': [ 'Infectious Diseases', 'Microbiology (medical)', 'General Immunology and Microbiology',
'Molecular Biology', 'Immunology and Allergy'],
'published': {'date-parts': [[2021, 6, 15]]}}
