Potential In Vitro Inhibition of Selected Plant Extracts against SARS-CoV-2 Chymotripsin-Like Protease (3CLPro) Activity
Carla Guijarro-Real, Mariola Plazas, Adrián Rodríguez-Burruezo, Jaime Prohens, Ana Fita
Foods, doi:10.3390/foods10071503
Antiviral treatments inhibiting Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication may represent a strategy complementary to vaccination to fight the ongoing Coronavirus disease 19 (COVID-19) pandemic. Molecules or extracts inhibiting the SARS-CoV-2 chymotripsin-like protease (3CL Pro ) could contribute to reducing or suppressing SARS-CoV-2 replication. Using a targeted approach, we identified 17 plant products that are included in current and traditional cuisines as promising inhibitors of SARS-CoV-2 3CL Pro activity. Methanolic extracts were evaluated in vitro for inhibition of SARS-CoV-2 3CL Pro activity using a quenched fluorescence resonance energy transfer (FRET) assay. Extracts from turmeric (Curcuma longa) rhizomes, mustard (Brassica nigra) seeds, and wall rocket (Diplotaxis erucoides subsp. erucoides) at 500 µg mL −1 displayed significant inhibition of the 3CL Pro activity, resulting in residual protease activities of 0.0%, 9.4%, and 14.9%, respectively. Using different extract concentrations, an IC 50 value of 15.74 µg mL −1 was calculated for turmeric extract. Commercial curcumin inhibited the 3CL Pro activity, but did not fully account for the inhibitory effect of turmeric rhizomes extracts, suggesting that other components of the turmeric extract must also play a main role in inhibiting the 3CL Pro activity. Sinigrin, a major glucosinolate present in mustard seeds and wall rocket, did not have relevant 3CL Pro inhibitory activity; however, its hydrolysis product allyl isothiocyanate had an IC 50 value of 41.43 µg mL −1 . The current study identifies plant extracts and molecules that can be of interest in the search for treatments against COVID-19, acting as a basis for future chemical, in vivo, and clinical trials.
This work is a first targeted approach for the evaluation of plant extracts and containing natural compounds for the development of prophylaxis, adjuvant therapies, and drug treatments aimed at inhibiting the activity of SARS-CoV-2 3CL Pro . Extracts of turmeric have been identified as a candidate plant extract for reducing SARS-CoV-2 3CL Pro activity, which could eventually affect the viral replication. In addition, other plant extracts, such as those of cruciferous plants containing sinigrin, which, after consumption, is degraded to allyl isothiocyanate, might be considered as well for their inhibition of SARS-CoV-2 3CL Pro activity. The current study provides information that can help in the search for treatments against COVID-19, acting as a basis for future chemical, in vivo, and clinical trials. Thus, further studies following the results of this work should be addressed: (1) to chemically characterize the plant extracts with high potential inhibitory activity and to re-evaluate this capacity after the fractionation of the extracts, thus allowing the identification of the biomolecules responsible of such activity and possible synergistic effects; and (2) to evaluate this potential inhibition in cell-based studies where the virus, host cell, and plant extract interact, also determining the toxicity limit prior to conducting other pre-clinical and clinical trials.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/..
References
Abian, Ortega-Alarcon, Jimenez-Alesanco, Ceballos-Laita, Vega et al., Structural stability of SARS-CoV-2 3CLpro and identification of quercetin as an inhibitor by experimental screening, Int. J. Biol. Macromol,
doi:10.1016/j.ijbiomac.2020.07.235Adem, Eyupoglu, Sarfraz, Rasul, Ali, Identification of potent COVID-19 main protease (M pro ) inhibitors from natural polyphenols: An in silico strategy unveils a hope against CORONA, Preprints,
doi:10.20944/preprints202003.0333.v1Agneta, Lelario, De Maria, Möllers, Bufo et al., Glucosinolate profile and distribution among plant tissues and phenological stages of field-grown horseradish, Phytochemistry,
doi:10.1016/j.phytochem.2014.06.019Astuti, Ysrafil, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): An overview of viral structure and host response, Diabetes Metab. Syndr. Clin. Res. Rev,
doi:10.1016/j.dsx.2020.04.020Blanchard, Elowe, Huitema, Fortin, Cechetto et al., High-throughput screening identifies inhibitors of the SARS Coronavirus Main Proteinase, Chem. Biol,
doi:10.1016/j.chembiol.2004.08.011Borges, Abreu, Ferreira, Saavedra, Simões et al., Antibacterial activity and mode of action of selected glucosinolate hydrolysis products against bacterial pathogens, J. Food Sci. Technol,
doi:10.1007/s13197-014-1533-1Borges-Argáez, Chan-Balan, Cetina-Montejo, Ayora-Talavera, Sansores-Peraza et al., In vitro evaluation of anthraquinones from Aloe vera (Aloe barbadensis Miller) roots and several derivatives against strains of influenza virus, Ind. Crops Prod,
doi:10.1016/j.indcrop.2019.02.056Chao, Wang, Li, Lin, Ye et al., Simultaneous quantification of three curcuminoids and three volatile components of Curcuma longa using pressurized liquid extraction and high-performance liquid chromatography, Molecules,
doi:10.3390/molecules23071568Chen, Lin, Huang, Chen, Hsieh et al., Inhibition of SARS-CoV 3C-like protease activity by theaflavin-3,3 -digallate (TF3), Evid. Based Complement. Altern. Med,
doi:10.1093/ecam/neh081Chen, Yiu, Wong, Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL pro ) structure: Virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates,
doi:10.12688/f1000research.22457.2Citi, Martelli, Brancaleone, Brogi, Gojon et al., Anti-inflammatory and antiviral roles of hydrogen sulfide: Rationale for considering H2S donors in COVID-19 therapy, Br. J. Pharmacol,
doi:10.1111/bph.15230Crozier, Lean, Mcdonald, Black, Quantitative Analysis of the Flavonoid Content of Commercial Tomatoes, Onions, Lettuce, and Celery, J. Agric. Food Chem,
doi:10.1021/jf960339yDe La Rosa, Ruiz-Palomino, Arriola-Guevara, García-Fajardo, Sandoval et al., A green process for the extraction and purification of hesperidin from mexican lime peel (Citrus aurantifolia Swingle) that is extendible to the citrus genus, Processes,
doi:10.3390/pr6120266Di Gioia, Avato, Serio, Argentieri, Glucosinolate profile of Eruca sativa, Diplotaxis tenuifolia and Diplotaxis erucoides grown in soil and soilless systems, J. Food Compos. Anal,
doi:10.1016/j.jfca.2018.01.022Doheny-Adams, Redeker, Kittipol, Bancroft, Hartley, Development of an efficient glucosinolate extraction method, Plant Methods,
doi:10.1186/s13007-017-0164-8El-Missiry, Fekri, Kesar, Othman, Polyphenols are potential nutritional adjuvants for targeting COVID-19, Phyther. Res,
doi:10.1002/ptr.6992Erlund, Review of the flavonoids quercetin, hesperetin, and naringenin. Dietary sources, bioactivities, bioavailability, and epidemiology, Nutr. Res,
doi:10.1016/j.nutres.2004.07.005Fahey, Zhang, Talalay, Broccoli sprouts: An exceptionally rich source of inducers of enzymes that protect against chemical carcinogens, Proc. Natl. Acad. Sci,
doi:10.1073/pnas.94.19.10367Forni, Mantovani, On Behalf of the COVID-19 Commission of Accademia Nazionale dei Lincei, Rome. COVID-19 vaccines: Where we stand and challenges ahead, Cell Death Differ,
doi:10.1038/s41418-020-00720-9Garcia-Castello, Rodriguez-Lopez, Mayor, Ballesteros, Conidi et al., Optimization of conventional and ultrasound assisted extraction of flavonoids from grapefruit (Citrus paradisi L.) solid wastes, LWT Food Sci. Technol,
doi:10.1016/j.lwt.2015.07.024Godos, Caraci, Castellano, Currenti, Galvano et al., Association between dietary flavonoids intake and cognitive function in an Italian cohort, Biomolecules,
doi:10.3390/biom10091300Guijarro-Real, Adalid-Martínez, Aguirre, Prohens, Rodríguez-Burruezo et al., Growing conditions affect the phytochemical composition of edible wall rocket (Diplotaxis erucoides), Agronomy,
doi:10.3390/agronomy9120858Guijarro-Real, Prohens, Rodriguez-Burruezo, Adalid-Martínez, López-Gresa et al., Wild edible fool's watercress, a potential crop with high nutraceutical properties, PeerJ,
doi:10.7717/peerj.6296Guijarro-Real, Prohens, Rodríguez-Burruezo, Fita, Consumers acceptance and volatile profile of wall rocket (Diplotaxis erucoides), Food Res. Int,
doi:10.1016/j.foodres.2020.109008Gurung, Ali, Lee, Farah, Al-Anazi, Unravelling lead antiviral phytochemicals for the inhibition of SARS-CoV-2 M pro enzyme through in silico approach, Life Sci,
doi:10.1016/j.lfs.2020.117831Gómez-Mejía, Rosales-Conrado, León-González, Madrid, Citrus peels waste as a source of value-added compounds: Extraction and quantification of bioactive polyphenols, Food Chem,
doi:10.1016/j.foodchem.2019.05.136Hilgenfeld, From SARS to MERS: Crystallographic studies on coronaviral proteases enable antiviral drug design, FEBS J,
doi:10.1111/febs.12936Hossain, Rai, Brunton, Martin-Diana, Barry-Ryan, Characterization of phenolic composition in lamiaceae spices by LC-ESI-MS/MS, J. Agric. Food Chem,
doi:10.1021/jf102042gIslam, Hoque, Rahman, Ul Alam, Akther et al., Genome-wide analysis of SARS-CoV-2 virus strains circulating worldwide implicates heterogeneity, Sci. Rep,
doi:10.1038/s41598-020-70812-6Justesen, Knuthsen, Composition of flavonoids in fresh herbs and calculation of flavonoid intake by use of herbs in traditional Danish dishes, Food Chem,
doi:10.1016/S0308-8146(01)00114-5Justesen, Knuthsen, Leth, Quantitative analysis of flavonols, flavones, and flavanones in fruits, vegetables and beverages by high performance liquid chromatography with photo-diode array and mass spectrometric detection, J. Chromatogr. A,
doi:10.1016/S0021-9673(97)01061-3Kaiser, Mutters, Blessing, Günther, Natural isothiocyanates express antimicrobial activity against developing and mature biofilms of Pseudomonas aeruginosa, Fitoterapia,
doi:10.1016/j.fitote.2017.04.006Khaerunnisa, Kurniawan, Awaluddin, Suhartati, Soetjipto, Potential inhibitor of COVID-19 Main Protease (M pro ) from several medicinal plant compounds by molecular docking study, Preprints,
doi:10.20944/preprints202003.0226.v1Kuo, Chi, Hsu, Liang, Characterization of SARS main protease and inhibitor assay using a fluorogenic substrate, Biochem. Biophys. Res. Commun,
doi:10.1016/j.bbrc.2004.04.098Laamarti, Alouane, Kartti, Chemao-Elfihri, Hakmi et al., Large scale genomic analysis of 3067 SARS-CoV-2 genomes reveals a clonal geodistribution and a rich genetic variations of hotspots mutations, PLoS ONE,
doi:10.1371/journal.pone.0240345Li, Kandhare, Mukherjee, Bodhankar, Acute and sub-chronic oral toxicity studies of hesperidin isolated from orange peel extract in Sprague Dawley rats, Regul. Toxicol. Pharmacol,
doi:10.1016/j.yrtph.2019.04.001Lin, Tsai, Tsai, Lai, Wan et al., Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds, Antivir. Res,
doi:10.1016/j.antiviral.2005.07.002Lin, Xiao, Zhao, Li, Xing et al., An overview of plant phenolic compounds and their importance in human nutrition and management of type 2 diabetes, Molecules,
doi:10.3390/molecules21101374Liu, Huang, Chao, Hsiao, Lin et al., Screening of drugs by FRET analysis identifies inhibitors of SARS-CoV 3CL protease, Biochem. Biophys. Res. Commun,
doi:10.1016/j.bbrc.2005.05.095López-Chillón, Carazo-Díaz, Prieto-Merino, Zafrilla, Moreno et al., Effects of long-term consumption of broccoli sprouts on inflammatory markers in overweight subjects, Clin. Nutr,
doi:10.1016/j.clnu.2018.03.006Manthey, Grohmann, Concentrations of hesperidin and other orange peel flavonoids in citrus processing byproducts, J. Agric. Food Chem,
doi:10.1021/jf950572gMartins, Barros, Ferreira, In vivo antioxidant activity of phenolic compounds: Facts and gaps, Trends Food Sci. Technol,
doi:10.1016/j.tifs.2015.11.008Martins, Barros, Santos-Buelga, Henriques, Silva et al., infusion and hydroalcoholic extract of Origanum vulgare L.: Different performances regarding bioactivity and phenolic compounds, Food Chem
Miean, Mohamed, Flavonoid (myricetin, quercetin, kaempferol, luteolin, and apigenin) content of edible tropical plants, J. Agric. Food Chem,
doi:10.1021/jf000892mNogata, Sakamoto, Shiratsuchi, Ishii, Yano et al., Flavonoid composition of fruit tissues of citrus species, Biosci. Biotechnol. Biochem,
doi:10.1271/bbb.70.178Olaimat, Al-Holy, Abu Ghoush, Al-Nabulsi, Holley, Control of Salmonella enterica and Listeria monocytogenes in hummus using allyl isothiocyanate, Int. J. Food Microbiol,
doi:10.1016/j.ijfoodmicro.2018.04.033Park, Yuk, Ryu, Lim, Kim et al., Evaluation of polyphenols from Broussonetia papyrifera as coronavirus protease inhibitors, J. Enzyme Inhib. Med. Chem,
doi:10.1080/14756366.2016.1265519Pendyala, Patrasa, In silico screening of food bioactive compounds to predict potential inhibitors of COVID-19 Main protease (M pro ) and RNA-dependent RNA polymerase (RdRp), ChemRxiv,
doi:10.26434/chemrxiv.12051927.v2Popović, Maravić, Čulić, Ðulović, Burčul et al., Biological effects of glucosinolate degradation products from horseradish: A horse that wins the race, Biomolecules,
doi:10.3390/biom10020343Rangkadilok, Nicolas, Bennett, Premier, Eagling et al., Developmental changes of sinigrin and glucoraphanin in three Brassica species (Brassica nigra, Brassica juncea and Brassica oleracea var. italica), Sci. Hortic
Romeo, Mesiti, Lupia, Alcaro, Current updates on naturally occurring compounds recognizing SARS-CoV-2 druggable targets, Molecules,
doi:10.3390/molecules26030632Ryu, Jeong, Kim, Kim, Park et al., Biflavonoids from Torreya nucifera displaying SARS-CoV 3CL pro inhibition, Bioorg. Med. Chem,
doi:10.1016/j.bmc.2010.09.035Schepici, Bramanti, Mazzon, Efficacy of sulforaphane in neurodegenerative diseases, Int. J. Mol. Sci,
doi:10.3390/ijms21228637Selmi, Rtibi, Grami, Sebai, Marzouki, Protective effects of orange (Citrus sinensis L.) peel aqueous extract and hesperidin on oxidative stress and peptic ulcer induced by alcohol in rat, Lipids Health Dis,
doi:10.1186/s12944-017-0546-ySepahpour, Selamat, Manap, Khatib, Razis, Comparative analysis of chemical composition, antioxidant activity and quantitative characterization of some phenolic compounds in selected herbs and spices in different solvent extraction systems, Molecules,
doi:10.3390/molecules23020402Shahawany, Al Hattab, Al Tahhan, Qualitative and Quantitative Analysis of Sinigrin in Different Parts In Vitro and In Vivo of Brassica nigra Plants, Biomed. Biotechnol,
doi:10.12691/bb-4-1-4Srivastava, Gupta, Characterization, Stability and Biological Activity of Flavonoids Isolated from Chamomile Flowers, Mol. Cell. Pharmacol,
doi:10.4255/mcpharmacol.09.18Srivastava, Xiao, Lew, Hershberger, Kokkinakis et al., Allyl isothiocyanate, a constituent of cruciferous vegetables, inhibits growth of PC-3 human prostate cancer xenograft in vivo, Carcinogenesis,
doi:10.1093/carcin/bgg123Svehlıkova, Bennett, Mellon, Needs, Piacente et al., Isolation, identification and stability of acylated derivatives of apigenin 7-O-glucoside from chamomile (Chamomilla recutita [L.] Rauschert), Phytochemistry,
doi:10.1016/j.phytochem.2004.07.011Sávio, Da Silva, Salvadori, Inhibition of bladder cancer cell proliferation by allyl isothiocyanate (mustard essential oil), Mutat. Res,
doi:10.1016/j.mrfmmm.2014.11.004Tsao, Yu, Potter, Chiba, Direct and simultaneous analysis of sinigrin and allyl isothiocyanate in mustard samples by high-performance liquid chromatography, J. Agric. Food Chem,
doi:10.1021/jf0200523Vougogiannopoulou, Corona, Tramontano, Alexis, Skaltsounis, Natural and nature-derived products targeting human coronaviruses, Molecules,
doi:10.3390/molecules26020448Wang, Chen, Gao, Hozumi, Yin et al., Analysis of SARS-CoV-2 mutations in the United States suggests presence of four substrains and novel variants, Commun. Biol,
doi:10.1038/s42003-021-01754-6Xi, Lu, Qun, Jiao, Characterization of phenolic profile and antioxidant capacity of different fruit part from lemon (Citrus limon Burm.) cultivars, J. Food Sci. Technol,
doi:10.1007/s13197-017-2544-5Xian, Zhang, Bian, Zhou, Zhang et al., Bioactive natural compounds against human coronaviruses: A review and perspective, Acta Pharm. Sin. B,
doi:10.1016/j.apsb.2020.06.002Xiao, Srivastava, Lew, Zeng, Hershberger et al., Allyl isothiocyanate, a constituent of cruciferous vegetables, inhibits proliferation of human prostate cancer cells by causing G2/M arrest and inducing apoptosis, Carcinogenesis,
doi:10.1093/carcin/bgg023Yang, Cheng, Zhang, Yaron, Jiang et al., Phenolic profiles, antioxidant, and antiproliferative activities of turmeric (Curcuma longa), Ind. Crops Prod,
doi:10.1016/j.indcrop.2020.112561Zhang, Duan, Zang, Huang, Liu, The flavonoid composition of flavedo and juice from the pummelo cultivar (Citrus grandis (L.) Osbeck) and the grapefruit cultivar (Citrus paradisi) from China, Food Chem,
doi:10.1016/j.foodchem.2011.05.136Zhang, Lin, Sun, Curth, Drosten et al., Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved a-ketoamide inhibitors, Science,
doi:10.1126/science.abb3405Zhou, Huang, Current Findings Regarding Natural Components with Potential Anti-2019-nCoV Activity, Front. Cell Dev. Biol,
doi:10.3389/fcell.2020.00589Zhou, Zheng, Li, Xu, Li et al., Natural polyphenols for prevention and treatment of cancer, Nutrients,
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'abstract': '<jats:p>Antiviral treatments inhibiting Severe acute respiratory syndrome coronavirus 2 '
'(SARS-CoV-2) replication may represent a strategy complementary to vaccination to fight the '
'ongoing Coronavirus disease 19 (COVID-19) pandemic. Molecules or extracts inhibiting the '
'SARS-CoV-2 chymotripsin-like protease (3CLPro) could contribute to reducing or suppressing '
'SARS-CoV-2 replication. Using a targeted approach, we identified 17 plant products that are '
'included in current and traditional cuisines as promising inhibitors of SARS-CoV-2 3CLPro '
'activity. Methanolic extracts were evaluated in vitro for inhibition of SARS-CoV-2 3CLPro '
'activity using a quenched fluorescence resonance energy transfer (FRET) assay. Extracts from '
'turmeric (Curcuma longa) rhizomes, mustard (Brassica nigra) seeds, and wall rocket '
'(Diplotaxis erucoides subsp. erucoides) at 500 µg mL−1 displayed significant inhibition of '
'the 3CLPro activity, resulting in residual protease activities of 0.0%, 9.4%, and 14.9%, '
'respectively. Using different extract concentrations, an IC50 value of 15.74 µg mL−1 was '
'calculated for turmeric extract. Commercial curcumin inhibited the 3CLPro activity, but did '
'not fully account for the inhibitory effect of turmeric rhizomes extracts, suggesting that '
'other components of the turmeric extract must also play a main role in inhibiting the 3CLPro '
'activity. Sinigrin, a major glucosinolate present in mustard seeds and wall rocket, did not '
'have relevant 3CLPro inhibitory activity; however, its hydrolysis product allyl '
'isothiocyanate had an IC50 value of 41.43 µg mL−1. The current study identifies plant '
'extracts and molecules that can be of interest in the search for treatments against COVID-19, '
'acting as a basis for future chemical, in vivo, and clinical trials.</jats:p>',
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{'key': 'ref3', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.dsx.2020.04.020'},
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'Knowhttps://www.who.int/news-room/feature-stories/detail/the-moderna-covid-19-mrna-1273-vaccine-what-you-need-to-know'},
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'series-title': 'COVID-19 Clinical Management. Living Guidance 25 January 2021',
'year': '2021'},
{'key': 'ref12', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/science.abb3405'},
{'key': 'ref13', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41598-020-79484-8'},
{'key': 'ref14', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.chembiol.2004.08.011'},
{'key': 'ref15', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/ecam/neh081'},
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{'key': 'ref18', 'doi-asserted-by': 'publisher', 'DOI': '10.1039/D0RA03774E'},
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{'key': 'ref27', 'doi-asserted-by': 'publisher', 'DOI': '10.1073/pnas.94.19.10367'},
{'key': 'ref28', 'doi-asserted-by': 'publisher', 'DOI': '10.2147/DDDT.S100534'},
{'key': 'ref29', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.clnu.2018.03.006'},
{'key': 'ref30', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/ijms21228637'},
{'key': 'ref31', 'doi-asserted-by': 'publisher', 'DOI': '10.4315/0362-028X-63.1.25'},
{'key': 'ref32', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.fitote.2017.04.006'},
{'key': 'ref33', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.bbrc.2005.05.095'},
{'key': 'ref34', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.bbrc.2004.04.098'},
{'key': 'ref35', 'doi-asserted-by': 'publisher', 'DOI': '10.1080/14756366.2016.1265519'},
{'key': 'ref36', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/agronomy9120858'},
{'key': 'ref37', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.foodres.2020.109008'},
{'key': 'ref38', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.nutres.2004.07.005'},
{'key': 'ref39', 'doi-asserted-by': 'publisher', 'DOI': '10.1021/jf950572g'},
{'key': 'ref40', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.yrtph.2019.04.001'},
{'key': 'ref41', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.lwt.2015.07.024'},
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{'key': 'ref67', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/978-1-4939-2438-7_1'},
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'series-title': 'Coronavirus Disease 2019 (COVID-19): Situation Report-94',
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{'key': 'ref69', 'doi-asserted-by': 'publisher', 'DOI': '10.1111/febs.12936'},
{'key': 'ref70', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.lfs.2020.117831'},
{'key': 'ref71', 'doi-asserted-by': 'publisher', 'DOI': '10.12688/f1000research.22457.2'},
{'key': 'ref72', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.bmc.2010.09.035'},
{'key': 'ref73', 'doi-asserted-by': 'publisher', 'DOI': '10.20944/preprints202002.0313.v1'},
{'key': 'ref74', 'doi-asserted-by': 'publisher', 'DOI': '10.20944/preprints202003.0214.v1'},
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{'key': 'ref76', 'doi-asserted-by': 'publisher', 'DOI': '10.26434/chemrxiv.12051927.v2'},
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