Liposomal Lactoferrin Exerts Antiviral Activity against HCoV-229E and SARS-CoV-2 Pseudoviruses In Vitro

{ 'indexed': {'date-parts': [[2023, 4, 18]], 'date-time': '2023-04-18T05:11:10Z', 'timestamp': 1681794670902}, 'reference-count': 39, 'publisher': 'MDPI AG', 'issue': '4', 'license': [ { 'start': { 'date-parts': [[2023, 4, 15]], 'date-time': '2023-04-15T00:00:00Z', 'timestamp': 1681516800000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0/'}], 'content-domain': {'domain': [], 'crossmark-restriction': False}, 'abstract': '<jats:p>A limited number of effective therapies are currently available to treat human ' 'coronavirus SARS-CoV-2 and other human coronaviruses, which are responsible for nearly a ' 'third of global cases of the common cold. The possibility of new emerging coronaviruses ' 'demands powerful new antiviral strategies. Lactoferrin is a well-known protein that possesses ' 'anti-inflammatory and immunomodulatory activities, and it has previously shown antiviral ' 'activity against several viruses, including SARS-CoV-2. To increase this antiviral activity, ' 'here we present bovine liposomal lactoferrin. Liposomal encapsulation of the compound was ' 'proven to increase permeability, bioavailability, and time release. In the present work, we ' 'compare the antiviral activity of free and liposomal bovine lactoferrin against HCoV229E and ' 'SARS-CoV-2 in vitro and in human primary bronchial epithelial cells, and we demonstrated that ' 'the liposomal form exerts a more potent antiviral activity than its free form at ' 'non-cytotoxic doses.</jats:p>', 'DOI': '10.3390/v15040972', 'type': 'journal-article', 'created': {'date-parts': [[2023, 4, 17]], 'date-time': '2023-04-17T08:45:32Z', 'timestamp': 1681721132000}, 'page': '972', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Liposomal Lactoferrin Exerts Antiviral Activity against HCoV-229E and SARS-CoV-2 Pseudoviruses ' 'In Vitro', 'prefix': '10.3390', 'volume': '15', 'author': [ { 'ORCID': 'http://orcid.org/0000-0003-0600-4152', 'authenticated-orcid': False, 'given': 'Sabina', 'family': 'Andreu', 'sequence': 'first', 'affiliation': [ { 'name': 'Department of Molecular Biology, Universidad Autónoma de Madrid, ' 'C/Darwin, 2 Cantoblanco, 28049 Madrid, Spain'}, { 'name': 'Centro de Biología Molecular Severo Ochoa, Spanish National ' 'Research Council—Universidad Autónoma de Madrid (CSIC-UAM), ' 'C/Nicolás Cabrera, 1 Cantoblanco, 28049 Madrid, Spain'}]}, { 'ORCID': 'http://orcid.org/0000-0001-7007-5401', 'authenticated-orcid': False, 'given': 'Inés', 'family': 'Ripa', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Molecular Biology, Universidad Autónoma de Madrid, ' 'C/Darwin, 2 Cantoblanco, 28049 Madrid, Spain'}, { 'name': 'Centro de Biología Molecular Severo Ochoa, Spanish National ' 'Research Council—Universidad Autónoma de Madrid (CSIC-UAM), ' 'C/Nicolás Cabrera, 1 Cantoblanco, 28049 Madrid, Spain'}]}, { 'ORCID': 'http://orcid.org/0000-0002-4415-6483', 'authenticated-orcid': False, 'given': 'Raquel', 'family': 'Bello-Morales', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Molecular Biology, Universidad Autónoma de Madrid, ' 'C/Darwin, 2 Cantoblanco, 28049 Madrid, Spain'}, { 'name': 'Centro de Biología Molecular Severo Ochoa, Spanish National ' 'Research Council—Universidad Autónoma de Madrid (CSIC-UAM), ' 'C/Nicolás Cabrera, 1 Cantoblanco, 28049 Madrid, Spain'}]}, { 'ORCID': 'http://orcid.org/0000-0003-2817-5956', 'authenticated-orcid': False, 'given': 'José Antonio', 'family': 'López-Guerrero', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Molecular Biology, Universidad Autónoma de Madrid, ' 'C/Darwin, 2 Cantoblanco, 28049 Madrid, Spain'}, { 'name': 'Centro de Biología Molecular Severo Ochoa, Spanish National ' 'Research Council—Universidad Autónoma de Madrid (CSIC-UAM), ' 'C/Nicolás Cabrera, 1 Cantoblanco, 28049 Madrid, Spain'}]}], 'member': '1968', 'published-online': {'date-parts': [[2023, 4, 15]]}, 'reference': [ { 'key': 'ref_1', 'doi-asserted-by': 'crossref', 'first-page': '536', 'DOI': '10.1038/s41564-020-0695-z', 'article-title': 'The Species Severe Acute Respiratory Syndrome-Related Coronavirus: ' 'Classifying 2019-NCoV and Naming It SARS-CoV-2', 'volume': '5', 'author': 'Gorbalenya', 'year': '2020', 'journal-title': 'Nat. Microbiol.'}, { 'key': 'ref_2', 'doi-asserted-by': 'crossref', 'first-page': '245', 'DOI': '10.1016/bs.aivir.2016.08.003', 'article-title': 'Molecular Basis of Coronavirus Virulence and Vaccine Development', 'volume': '96', 'author': 'Enjuanes', 'year': '2016', 'journal-title': 'Adv. Virus Res.'}, { 'key': 'ref_3', 'doi-asserted-by': 'crossref', 'first-page': '7577', 'DOI': '10.1128/JVI.00269-12', 'article-title': 'A Human Coronavirus Responsible for the Common Cold Massively Kills ' 'Dendritic Cells but Not Monocytes', 'volume': '86', 'author': 'Millet', 'year': '2012', 'journal-title': 'J. Virol.'}, { 'key': 'ref_4', 'doi-asserted-by': 'crossref', 'unstructured': 'Menéndez, J.C. (2022). Approaches to the Potential Therapy of COVID-19: ' 'A General Overview from the Medicinal Chemistry Perspective. Molecules, ' '27.', 'DOI': '10.3390/molecules27030658'}, { 'key': 'ref_5', 'doi-asserted-by': 'crossref', 'first-page': '286', 'DOI': '10.1080/01480545.2019.1585868', 'article-title': 'Anti-Inflammatory, Anti-Oxidant and Hepatoprotective Effects of ' 'Lactoferrin in Rats', 'volume': '44', 'author': 'Farid', 'year': '2019', 'journal-title': 'Drug Chem. Toxicol.'}, { 'key': 'ref_6', 'doi-asserted-by': 'crossref', 'unstructured': 'Kopaeva, M.Y., Alchinova, I.B., Cherepov, A.B., Demorzhi, M.S., ' 'Nesterenko, M.V., Zarayskaya, I.Y., and Karganov, M.Y. (2022). New ' 'Properties of a Well-Known Antioxidant: Pleiotropic Effects of Human ' 'Lactoferrin in Mice Exposed to Gamma Irradiation in a Sublethal Dose. ' 'Antioxidants, 11.', 'DOI': '10.3390/antiox11091833'}, { 'key': 'ref_7', 'doi-asserted-by': 'crossref', 'first-page': '282', 'DOI': '10.1139/o06-045', 'article-title': 'Interactions of Lactoferrin with Cells Involved in Immune Function', 'volume': '84', 'author': 'Legrand', 'year': '2006', 'journal-title': 'Biochem. Cell Biol.'}, { 'key': 'ref_8', 'doi-asserted-by': 'crossref', 'unstructured': 'Berlutti, F., Pantanella, F., Natalizi, T., Frioni, A., Paesano, R., ' 'Polimeni, A., and Valenti, P. (2011). Antiviral Properties of ' 'Lactoferrin—A Natural Immunity Molecule. Molecules, 16.', 'DOI': '10.3390/molecules16086992'}, { 'key': 'ref_9', 'first-page': '08', 'article-title': 'Liposomal Lactoferrin as Potential Preventative and Cure for COVID-19', 'volume': '8', 'author': 'Serrano', 'year': '2020', 'journal-title': 'Int. J. Res. Health Sci.'}, { 'key': 'ref_10', 'doi-asserted-by': 'crossref', 'unstructured': 'Einerhand, A.W.C., van Loo-Bouwman, C.A., Weiss, G.A., Wang, C., Ba, G., ' 'Fan, Q., He, B., and Smit, G. (2022). Can Lactoferrin, a Natural ' 'Mammalian Milk Protein, Assist in the Battle against COVID-19?. ' 'Nutrients, 14.', 'DOI': '10.3390/nu14245274'}, { 'key': 'ref_11', 'doi-asserted-by': 'crossref', 'first-page': '580', 'DOI': '10.1080/10408398.2017.1381583', 'article-title': 'Lactoferrin: Structure, Function, Denaturation and Digestion', 'volume': '59', 'author': 'Wang', 'year': '2019', 'journal-title': 'Crit. Rev. Food Sci. Nutr.'}, { 'key': 'ref_12', 'doi-asserted-by': 'crossref', 'unstructured': 'Bolat, E., Eker, F., Kaplan, M., Duman, H., Arslan, A., Saritaş, S., ' 'Şahutoğlu, A.S., and Karav, S. (2022). Lactoferrin for COVID-19 ' 'Prevention, Treatment, and Recovery. Front. Nutr., 9.', 'DOI': '10.3389/fnut.2022.992733'}, { 'key': 'ref_13', 'doi-asserted-by': 'crossref', 'unstructured': 'Lang, J., Yang, N., Deng, J., Liu, K., Yang, P., Zhang, G., and Jiang, ' 'C. (2011). Inhibition of SARS Pseudovirus Cell Entry by Lactoferrin ' 'Binding to Heparan Sulfate Proteoglycans. PLoS ONE, 6.', 'DOI': '10.1371/journal.pone.0023710'}, { 'key': 'ref_14', 'doi-asserted-by': 'crossref', 'unstructured': 'He, S.T., Qin, H., Guan, L., Liu, K., Hong, B., Zhang, X., Lou, F., Li, ' 'M., Lin, W., and Chen, Y. (2023). Bovine Lactoferrin Inhibits SARS-CoV-2 ' 'and SARS-CoV-1 by Targeting the RdRp Complex and Alleviates Viral ' 'Infection in the Hamster Model. J. Med. Virol., 95.', 'DOI': '10.1002/jmv.28281'}, { 'key': 'ref_15', 'first-page': '16', 'article-title': 'Liposomal Lactoferrin Effect in Preventing SARS-CoV-2 Binding in HACAT ' 'Keratinocytes', 'volume': '8', 'author': 'Serrano', 'year': '2020', 'journal-title': 'Int. J. Res. Health Sci.'}, { 'key': 'ref_16', 'doi-asserted-by': 'crossref', 'unstructured': 'Campione, E., Lanna, C., Cosio, T., Rosa, L., Conte, M.P., Iacovelli, ' 'F., Romeo, A., Falconi, M., Del Vecchio, C., and Franchin, E. (2021). ' 'Lactoferrin as Antiviral Treatment in COVID-19 Management: Preliminary ' 'Evidence. Int J. Environ. Res. Public Health, 18.', 'DOI': '10.3390/ijerph182010985'}, { 'key': 'ref_17', 'doi-asserted-by': 'crossref', 'first-page': '1717', 'DOI': '10.1248/bpb.28.1717', 'article-title': 'Liposomalization of Lactoferrin Enhanced It’s Anti-Inflammatory Effects ' 'via Oral Administration', 'volume': '28', 'author': 'Ishikado', 'year': '2005', 'journal-title': 'Biol. Pharm. Bull.'}, { 'key': 'ref_18', 'first-page': '559', 'article-title': 'Liposomes as Possible Carriers for Lactoferrin in the Local Treatment ' 'of Inflammatory Diseases', 'volume': '226', 'author': 'Trie', 'year': '2016', 'journal-title': 'Exp. Biol. Med.'}, { 'key': 'ref_19', 'doi-asserted-by': 'crossref', 'first-page': '237', 'DOI': '10.1080/08982100701530027', 'article-title': 'Designing Lipid Nanostructures for Local Delivery of Biologically ' 'Active Macromolecules', 'volume': '17', 'author': 'Trif', 'year': '2008', 'journal-title': 'J. Liposome Res.'}, { 'key': 'ref_20', 'doi-asserted-by': 'crossref', 'unstructured': 'Liu, P., Chen, G., and Zhang, J. (2022). A Review of Liposomes as a Drug ' 'Delivery System: Current Status of Approved Products, Regulatory ' 'Environments, and Future Perspectives. Molecules, 27.', 'DOI': '10.3390/molecules27041372'}, { 'key': 'ref_21', 'first-page': '3858', 'article-title': 'Growth of Human Hepatoma Cells Lines with Differentiated Functions in ' 'Chemically Defined Medium', 'volume': '42', 'author': 'Nakabayashi', 'year': '1982', 'journal-title': 'Cancer Res.'}, { 'key': 'ref_22', 'doi-asserted-by': 'crossref', 'first-page': 'e13549', 'DOI': '10.15252/emmm.202013549', 'article-title': 'Flow Cytometry Multiplexed Method for the Detection of Neutralizing ' 'Human Antibodies to the Native SARS-CoV-2.2 Spike Prot.tein', 'volume': '13', 'author': 'Horndler', 'year': '2021', 'journal-title': 'EMBO Mol. Med.'}, { 'key': 'ref_23', 'doi-asserted-by': 'crossref', 'unstructured': 'Grau-Expósito, J., Perea, D., Suppi, M., Massana, N., Vergara, A., ' 'Soler, M.J., Trinite, B., Blanco, J., García-Pérez, J., and Alcamí, J. ' '(2022). Evaluation of SARS-CoV-2 Entry, Inflammation and New ' 'Therapeutics in Human Lung Tissue Cells. PLoS Pathog., 18.', 'DOI': '10.1371/journal.ppat.1010171'}, { 'key': 'ref_24', 'doi-asserted-by': 'crossref', 'first-page': '493', 'DOI': '10.1093/oxfordjournals.aje.a118408', 'article-title': 'A Simple Method of Estimating Fifty per Cent Endpoints', 'volume': '27', 'author': 'Reed', 'year': '1938', 'journal-title': 'Am. J. Epidemiol.'}, { 'key': 'ref_25', 'doi-asserted-by': 'crossref', 'unstructured': 'Andreu, S., Ripa, I., Praena, B., López-guerrero, J.A., and ' 'Bello-morales, R. (2021). The Valproic Acid Derivative Valpromide ' 'Inhibits Pseudorabies Virus Infection in Swine Epithelial and Mouse ' 'Neuroblastoma Cell Lines. Viruses, 13.', 'DOI': '10.3390/v13122522'}, { 'key': 'ref_26', 'first-page': '591', 'article-title': 'Phosphatidylcholine Liposomes as Carriers to Improve Topical Ascorbic ' 'Acid Treatment of Skin Disorders', 'volume': '8', 'author': 'Serrano', 'year': '2015', 'journal-title': 'Clin. Cosmet. Investig. Dermatol.'}, { 'key': 'ref_27', 'doi-asserted-by': 'crossref', 'first-page': '255', 'DOI': '10.1002/fsn3.388', 'article-title': 'A Nutritional Supplement Containing Lactoferrin Stimulates the Immune ' 'System, Extends Lifespan, and Reduces Amyloid β Peptide Toxicity in ' 'Caenorhabditis Elegans', 'volume': '5', 'author': 'Martorell', 'year': '2017', 'journal-title': 'Food Sci. Nutr.'}, { 'key': 'ref_28', 'doi-asserted-by': 'crossref', 'first-page': '103255', 'DOI': '10.1016/j.ebiom.2021.103255', 'article-title': 'Camostat Mesylate Inhibits SARS-CoV-2 Activation by TMPRSS2-Related ' 'Proteases and Its Metabolite GBPA Exerts Antiviral Activi.ity', 'volume': '65', 'author': 'Hoffmann', 'year': '2021', 'journal-title': 'EBioMedicine'}, { 'key': 'ref_29', 'doi-asserted-by': 'crossref', 'first-page': '317', 'DOI': '10.1080/22221751.2021.1888660', 'article-title': 'The in Vitro Antiviral Activity of Lactoferrin against Common Human ' 'Coronaviruses and SARS-CoV-2 Is Mediated by Targeting the Heparan ' 'Sulfate Co-Receptor', 'volume': '10', 'author': 'Hu', 'year': '2021', 'journal-title': 'Emerg Microbes Infect.'}, { 'key': 'ref_30', 'doi-asserted-by': 'crossref', 'unstructured': 'Sokolov, A.V., Isakova-Sivak, I.N., Mezhenskaya, D.A., Kostevich, V.A., ' 'Gorbunov, N.P., Elizarova, A.Y., Matyushenko, V.A., Berson, Y.M., ' 'Grudinina, N.A., and Kolmakov, N.N. (2022). Molecular Mimicry of the ' 'Receptor-Binding Domain of the SARS-CoV-2 Spike Protein: From the ' 'Interaction of Spike-Specific Antibodies with Transferrin and ' 'Lactoferrin to the Antiviral Effects of Human Recombinant Lactoferrin. ' 'Biometals, 1–26.', 'DOI': '10.1007/s10534-022-00458-6'}, { 'key': 'ref_31', 'doi-asserted-by': 'crossref', 'unstructured': 'Sokolov, A., Isakova-Sivak, I., Grudinina, N., Mezhenskaya, D., ' 'Litasova, E., Kostevich, V., Stepanova, E., Rak, A., Sychev, I., and ' 'Kirik, O. (2022). Ferristatin II Efficiently Inhibits SARS-CoV-2 ' 'Replication in Vero Cells. Viruses, 14.', 'DOI': '10.3390/v14020317'}, { 'key': 'ref_32', 'doi-asserted-by': 'crossref', 'unstructured': 'Cutone, A., Rosa, L., Bonaccorsi di Patti, M.C., Iacovelli, F., Conte, ' 'M.P., Ianiro, G., Romeo, A., Campione, E., Bianchi, L., and Valenti, P. ' '(2022). Lactoferrin Binding to SARS-CoV-2 Spike Glycoprotein Blocks ' 'Pseudoviral Entry and Relieves Iron Protein Dysregulation in Several In ' 'Vitro Models. Pharmaceutics, 14.', 'DOI': '10.21203/rs.3.rs-1605740/v1'}, { 'key': 'ref_33', 'doi-asserted-by': 'crossref', 'first-page': '609', 'DOI': '10.2217/fvl-2020-0170', 'article-title': 'The Potential of Lactoferrin, Ovotransferrin and Lysozyme as Antiviral ' 'and Immune-Modulating Agents in COVID-19', 'volume': '15', 'author': 'Mann', 'year': '2020', 'journal-title': 'Future Virol.'}, { 'key': 'ref_34', 'doi-asserted-by': 'crossref', 'first-page': '1466', 'DOI': '10.1080/09205063.2021.1925391', 'article-title': 'The Non-Specific Antiviral Activity of Polysulfates to Fight ' 'SARS-CoV-2, Its Mutants and Viruses with Cationic Spikes', 'volume': '32', 'author': 'Vert', 'year': '2021', 'journal-title': 'J. Biomater. Sci. Polym. Ed.'}, { 'key': 'ref_35', 'unstructured': 'US Food and Drug Administration (2023, March 05). GRN 000456 Cow’s ' 'Milk-Derived Lactoferrin, Available online: ' 'https://www.fda.gov/media/153787/download.'}, { 'key': 'ref_36', 'doi-asserted-by': 'crossref', 'first-page': '557', 'DOI': '10.1038/aps.2013.200', 'article-title': 'Immunomodulatory Effects of Lactoferrin', 'volume': '35', 'year': '2014', 'journal-title': 'Acta Pharmacol. Sin.'}, { 'key': 'ref_37', 'doi-asserted-by': 'crossref', 'unstructured': 'Salaris, C., Scarpa, M., Elli, M., Bertolini, A., Guglielmetti, S., ' 'Pregliasco, F., Blandizzi, C., Brun, P., and Castagliuolo, I. (2021). ' 'Protective Effects of Lactoferrin against SARS-CoV-2 Infection In Vitro. ' 'Nutrients, 13.', 'DOI': '10.3390/nu13020328'}, { 'key': 'ref_38', 'doi-asserted-by': 'crossref', 'first-page': '272', 'DOI': '10.3892/etm.2020.9402', 'article-title': 'Lactoferrin for the Treatment of COVID-19 (Review)', 'volume': '20', 'author': 'Wang', 'year': '2020', 'journal-title': 'Exp. Ther. Med.'}, { 'key': 'ref_39', 'doi-asserted-by': 'crossref', 'first-page': '273', 'DOI': '10.1016/bs.podrm.2020.07.005', 'article-title': 'Validation of In-Vitro Bioassay Methods: Application in Herbal Drug ' 'Research', 'volume': '46', 'author': 'Indrayanto', 'year': '2021', 'journal-title': 'Profiles Drug Subst. Excip. Relat. Methodol.'}], 'container-title': 'Viruses', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://www.mdpi.com/1999-4915/15/4/972/pdf', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2023, 4, 17]], 'date-time': '2023-04-17T09:08:14Z', 'timestamp': 1681722494000}, 'score': 1, 'resource': {'primary': {'URL': 'https://www.mdpi.com/1999-4915/15/4/972'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2023, 4, 15]]}, 'references-count': 39, 'journal-issue': {'issue': '4', 'published-online': {'date-parts': [[2023, 4]]}}, 'alternative-id': ['v15040972'], 'URL': 'http://dx.doi.org/10.3390/v15040972', 'relation': {}, 'ISSN': ['1999-4915'], 'subject': ['Virology', 'Infectious Diseases'], 'container-title-short': 'Viruses', 'published': {'date-parts': [[2023, 4, 15]]}}