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Previously, 3-hydroxyphthalic anhydride-modified bovine \u03b2-lactoglobulin (3HP-\u03b2-LG) was proven to be effective against human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and it has also been used in the clinical control of cervical human papillomavirus (HPV) infections. Here, we show its efficacy in potently inhibiting infection by divergent influenza A and B viruses. Mechanistic studies suggest that 3HP-\u03b2-LG binds, possibly through its negatively charged residues, to the receptor-binding domain in the hemagglutinin 1 (HA1) subunit in the HA of the influenza virus, thus inhibiting the attachment of the HA to sialic acid on host cells. The intranasal administration of 3HP-\u03b2-LG led to the protection of mice against challenges by influenza A(H1N1)\/PR8, A(H3N2), and A(H7N9) viruses. Furthermore, 3HP-\u03b2-LG is highly stable when stored at 50 \u00b0C for 30 days and it shows excellent safety in vitro and in vivo. Collectively, our findings suggest that 3HP-\u03b2-LG could be successfully repurposed as an intranasal prophylactic agent to prevent influenza virus infections during influenza outbreaks.<\/jats:p>","DOI":"10.3390\/v14092055","type":"journal-article","created":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T00:08:09Z","timestamp":1663718889000},"page":"2055","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Chemically Modified Bovine \u03b2-Lactoglobulin as a Broad-Spectrum Influenza Virus Entry Inhibitor with the Potential to Combat Influenza Outbreaks"],"prefix":"10.3390","volume":"14","author":[{"given":"Yuhong","family":"Fu","sequence":"first","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology of MOE\/MOH, School of Basic Medical Sciences, Shanghai Public Health Clinical Center, Fudan University, 131 Dong An Rd., Xuhui District, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyu","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology of MOE\/MOH, School of Basic Medical Sciences, Shanghai Public Health Clinical Center, Fudan University, 131 Dong An Rd., Xuhui District, Shanghai 200032, China"},{"name":"Department of Infectious Diseases and Shenzhen Key Laboratory for Endogenous Infection, Shenzhen Nanshan People\u2019s Hospital and the Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen 518052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3013-7182","authenticated-orcid":false,"given":"Wei","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology of MOE\/MOH, School of Basic Medical Sciences, Shanghai Public Health Clinical Center, Fudan University, 131 Dong An Rd., Xuhui District, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zezhong","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology of MOE\/MOH, School of Basic Medical Sciences, Shanghai Public Health Clinical Center, Fudan University, 131 Dong An Rd., Xuhui District, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology of MOE\/MOH, School of Basic Medical Sciences, Shanghai Public Health Clinical Center, Fudan University, 131 Dong An Rd., Xuhui District, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5322-0283","authenticated-orcid":false,"given":"Qian","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology of MOE\/MOH, School of Basic Medical Sciences, Shanghai Public Health Clinical Center, Fudan University, 131 Dong An Rd., Xuhui District, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Tang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology of MOE\/MOH, School of Basic Medical Sciences, Shanghai Public Health Clinical Center, Fudan University, 131 Dong An Rd., Xuhui District, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weihua","family":"Li","sequence":"additional","affiliation":[{"name":"NHC Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), Fudan University, 2140 Xie Tu Rd., Xuhui District, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2255-0391","authenticated-orcid":false,"given":"Lu","family":"Lu","sequence":"additional","affiliation":[{"name":"Key Laboratory of 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Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1126\/science.aaq0620","article-title":"Universal protection against influenza infection by a multidomain antibody to influenza hemagglutinin","volume":"362","author":"Laursen","year":"2018","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"D49","DOI":"10.1016\/j.vaccine.2008.07.039","article-title":"The biology of influenza viruses","volume":"26","author":"Bouvier","year":"2008","journal-title":"Vaccine"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"352","DOI":"10.3390\/v5010352","article-title":"Influenza A virus entry inhibitors targeting the hemagglutinin","volume":"5","author":"Yang","year":"2013","journal-title":"Viruses"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1073\/pnas.1524384113","article-title":"Molecular requirements for a pandemic influenza virus: An acid-stable hemagglutinin protein","volume":"113","author":"Russier","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1038\/s41586-020-2333-6","article-title":"Structural transitions in influenza haemagglutinin at membrane fusion pH","volume":"583","author":"Benton","year":"2020","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1080\/14656566.2020.1856814","article-title":"Emerging and state of the art hemagglutinin-targeted influenza virus inhibitors","volume":"22","author":"Zhang","year":"2021","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/jac\/dkq387","article-title":"Phenotypic and genotypic characterization of influenza virus mutants selected with the sialidase fusion protein DAS181","volume":"66","author":"Sanders","year":"2011","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"105013","DOI":"10.1016\/j.antiviral.2021.105013","article-title":"Identification of a novel inhibitor targeting influenza A virus group 2 hemagglutinins","volume":"186","author":"Du","year":"2021","journal-title":"Antivir. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2654","DOI":"10.1038\/s41467-021-22964-w","article-title":"Macrocyclic peptides exhibit antiviral effects against influenza virus HA and prevent pneumonia in animal models","volume":"12","author":"Saito","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1586\/14787210.2014.966083","article-title":"A review of neuraminidase inhibitor susceptibility in influenza strains","volume":"12","author":"Spanakis","year":"2014","journal-title":"Expert Rev. Anti Infect. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0166-3542(00)00103-0","article-title":"Resistance of influenza viruses to neuraminidase inhibitors\u2014A review","volume":"47","year":"2000","journal-title":"Antivir. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.1056\/NEJMoa054512","article-title":"Oseltamivir resistance during treatment of influenza A (H5N1) infection","volume":"353","author":"Tran","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1002\/jmv.24439","article-title":"Safety evaluation of chemically modified beta-lactoglobulin administered intravaginally","volume":"88","author":"Guo","year":"2016","journal-title":"J. Med. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.micinf.2015.10.004","article-title":"A randomized open-label clinical trial of an anti-HPV biological dressing (JB01-BD) administered intravaginally to treat high-risk HPV infection","volume":"18","author":"Guo","year":"2016","journal-title":"Microbes Infect."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/s41392-021-00737-7","article-title":"Repurposing of a clinically used anti-HPV agent to prevent and treat SARS-CoV-2 infection as an intranasal formulation","volume":"6","author":"Hua","year":"2021","journal-title":"Signal. Transduct. Target. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/j.micinf.2013.03.003","article-title":"Chemically modified bovine beta-lactoglobulin inhibits human papillomavirus infection","volume":"15","author":"Lu","year":"2013","journal-title":"Microbes Infect."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/nm0296-230","article-title":"Bovine beta-lactoglobulin modified by 3-hydroxyphthalic anhydride blocks the CD4 cell receptor for HIV","volume":"2","author":"Neurath","year":"1996","journal-title":"Nat. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1016\/S0140-6736(96)91539-1","article-title":"A herpesvirus inhibitor from bovine whey","volume":"347","author":"Neurath","year":"1996","journal-title":"Lancet"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1128\/JVI.02344-12","article-title":"Identification and structural characterization of a broadly neutralizing antibody targeting a novel conserved epitope on the influenza virus H5N1 hemagglutinin","volume":"87","author":"Du","year":"2013","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1016\/j.bbrc.2010.05.161","article-title":"Development of a safe and convenient neutralization assay for rapid screening of influenza HA-specific neutralizing monoclonal antibodies","volume":"397","author":"Du","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.3201\/eid1910.130728","article-title":"Safe pseudovirus-based assay for neutralization antibodies against influenza A(H7N9) virus","volume":"19","author":"Qiu","year":"2013","journal-title":"Emerg. Infect. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2831","DOI":"10.1080\/21645515.2015.1074363","article-title":"Intranasal vaccination of recombinant H5N1 HA1 proteins fused with foldon and Fc induces strong mucosal immune responses with neutralizing activity: Implication for developing novel mucosal influenza vaccines","volume":"11","author":"Yu","year":"2015","journal-title":"Hum. Vaccin. Immunother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/1742-4690-7-37","article-title":"Maleic anhydride-modified chicken ovalbumin as an effective and inexpensive anti-HIV microbicide candidate for prevention of HIV sexual transmission","volume":"7","author":"Li","year":"2010","journal-title":"Retrovirology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"798","DOI":"10.3390\/v7020798","article-title":"Intranasal administration of maleic anhydride-modified human serum albumin for pre-exposure prophylaxis of respiratory syncytial virus infection","volume":"7","author":"Sun","year":"2015","journal-title":"Viruses"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/0003-2697(80)90006-8","article-title":"Modification of available arginine residues in proteins by p-hydroxyphenylglyoxal","volume":"109","author":"Yamasaki","year":"1980","journal-title":"Anal. Biochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1099\/jgv.0.000365","article-title":"Putative suppressing effect of IgG Fc-conjugated haemagglutinin (HA) stalk of influenza virus H7N9 on the neutralizing immunogenicity of Fc-conjugated HA head: Implication for rational design of HA-based influenza vaccines","volume":"97","author":"He","year":"2016","journal-title":"J. Gen. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2643","DOI":"10.3389\/fmicb.2018.02643","article-title":"The Antihistamine Drugs Carbinoxamine Maleate and Chlorpheniramine Maleate Exhibit Potent Antiviral Activity Against a Broad Spectrum of Influenza Viruses","volume":"9","author":"Xu","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0065-2571(84)90007-4","article-title":"Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors","volume":"22","author":"Chou","year":"1984","journal-title":"Adv. Enzyme Regul."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3294","DOI":"10.4049\/jimmunol.0900398","article-title":"Original antigenic sin responses to influenza viruses","volume":"183","author":"Kim","year":"2009","journal-title":"J. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.bcp.2017.07.023","article-title":"Potent influenza A virus entry inhibitors targeting a conserved region of hemagglutinin","volume":"144","author":"Lin","year":"2017","journal-title":"Biochem. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1179\/2047773212Y.0000000004","article-title":"Bovine lactoferrin-derived peptides as novel broad-spectrum inhibitors of influenza virus","volume":"106","author":"Ammendolia","year":"2012","journal-title":"Pathog. Glob. Health."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1139\/o11-072","article-title":"Bovine lactoferrin: Involvement of metal saturation and carbohydrates in the inhibition of influenza virus infection","volume":"90","author":"Pietrantoni","year":"2012","journal-title":"Biochem. Cell Biol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Kubo, S., Miyakawa, M., Tada, A., Oda, H., Motobayashi, H., Iwabuchi, S., Tamura, S., Tanaka, M., and Hashimoto, S. (2022). Lactoferrin and its digestive peptides induce interferon-alpha production and activate plasmacytoid dendritic cells ex vivo. Biometals.","DOI":"10.1007\/s10534-022-00436-y"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"547","DOI":"10.3168\/jds.S0022-0302(07)71538-2","article-title":"Antioxidant nature of bovine milk beta-lactoglobulin","volume":"90","author":"Liu","year":"2007","journal-title":"J. Dairy Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1021\/jf970692j","article-title":"Thiol Reactivity in Pressure-Unfolded beta-Lactoglobulin. Antioxidative Properties and Thermal Refolding","volume":"46","author":"Moller","year":"1998","journal-title":"J. Agric. Food Chem."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/9\/2055\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:32:44Z","timestamp":1760142764000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/9\/2055"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,16]]},"references-count":36,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["v14092055"],"URL":"https:\/\/doi.org\/10.3390\/v14092055","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,16]]}}}