{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T17:05:17Z","timestamp":1790528717332,"version":"4.1.0"},"reference-count":34,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2018,12,14]],"date-time":"2018-12-14T00:00:00Z","timestamp":1544745600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Influenza A virus (IAV) infection is still a major global threat for humans, especially for the risk groups: young children and the elderly. The currently licensed antiviral drugs target viral factors and are prone to viral resistance. In recent years, a few endogenous small molecules from host, such as estradiol and omega-3 polyunsaturated fatty acid (PUFA)-derived lipid mediator protection D1 (PD1), were demonstrated to be capable of inhibiting IAV infection. Chenodeoxycholic acid (CDCA), one of the main primary bile acids, is synthesized from cholesterol in the liver and classically functions in emulsification and absorption of dietary fats. Clinically, CDCA has been used in the treatment of patients with cholesterol gallstones for more than five decades. In this study, we showed that CDCA attenuated the replication of three subtypes of influenza A virus, including a highly pathogenic H5N1 strain, in A549 and MDCK cell cultures with IC50 ranging from 5.5 to 11.5 \u03bcM. Mechanistically, CDCA effectively restrained the nuclear export of viral ribonucleoprotein (vRNP) complexes. In conclusion, as an endogenous physiological small molecule, CDCA can inhibit IAV replication in vitro, at least in part, by blocking vRNP nuclear export, and affords further studies for development as a potential antiviral agent against IAV infections.<\/jats:p>","DOI":"10.3390\/molecules23123315","type":"journal-article","created":{"date-parts":[[2018,12,14]],"date-time":"2018-12-14T04:44:42Z","timestamp":1544762682000},"page":"3315","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Chenodeoxycholic Acid from Bile Inhibits Influenza A Virus Replication via Blocking Nuclear Export of Viral Ribonucleoprotein Complexes"],"prefix":"10.3390","volume":"23","author":[{"given":"Ling","family":"Luo","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weili","family":"Han","sequence":"additional","affiliation":[{"name":"Hygiene Detection Center, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyan","family":"Du","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Yang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mubing","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC  3086, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenggang","family":"Xu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenling","family":"Zeng","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5221-9771","authenticated-orcid":false,"given":"Weisan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC  3086, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianxin","family":"Chen","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,12,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1001\/jama.292.11.1333","article-title":"Influenza-associated hospitalizations in the United States","volume":"292","author":"Thompson","year":"2004","journal-title":"Jama"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"20657","DOI":"10.2807\/1560-7917.ES2013.18.50.20657","article-title":"Kinetics of serological responses in influenza a(h7n9)-infected patients correlate with clinical outcome in China, 2013","volume":"18","author":"Zhang","year":"2013","journal-title":"Eurosurveillance"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1056\/NEJMra052211","article-title":"Avian influenza a (h5n1) infection in humans","volume":"353","author":"Beigel","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.3201\/eid1510.091186","article-title":"Poor clinical sensitivity of rapid antigen test for influenza a pandemic (h1n1) 2009 virus","volume":"15","author":"Drexler","year":"2009","journal-title":"Emerg. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1093\/infdis\/jis337","article-title":"Characteristics of a widespread community cluster of H275Y oseltami-vir-resistant A(H1N1)pdm09 influenza in Australia","volume":"206","author":"Hurt","year":"2012","journal-title":"J. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1056\/NEJMc1111078","article-title":"Community transmission of oseltamivir-resistant a(h1n1)pdm09 influenza","volume":"365","author":"Hurt","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.4049\/jimmunol.1200168","article-title":"Rapid differentiation of monocytes into type i ifn-producing myeloid dendritic cells as an antiviral strategy against influenza virus infection","volume":"189","author":"Cao","year":"2012","journal-title":"J. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11229","DOI":"10.1128\/JVI.00727-14","article-title":"Histone deacetylase 6 inhibits influenza a virus release by downregulating the trafficking of viral components to the plasma membrane via its substrate, acetylated microtubules","volume":"88","author":"Husain","year":"2014","journal-title":"J. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"22015","DOI":"10.1074\/jbc.M111.319996","article-title":"Influenza virus partially counteracts restriction imposed by tetherin\/bst-2","volume":"287","author":"Mangeat","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3314","DOI":"10.1093\/nar\/gkt019","article-title":"Mcpip1 ribonuclease exhibits broad-spectrum antiviral effects through viral rna binding and degradation","volume":"41","author":"Lin","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.cell.2013.02.027","article-title":"The lipid mediator protectin d1 inhibits influenza virus replication and improves severe influenza","volume":"153","author":"Morita","year":"2013","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1136\/gut.27.10.1232-b","article-title":"Sterols and bile acids","volume":"27","author":"Makin","year":"1986","journal-title":"Gut"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"804","DOI":"10.3748\/wjg.15.804","article-title":"Bile acids: Chemistry, physiology, and pathophysiology","volume":"15","author":"Monte","year":"2009","journal-title":"World J. Gastroenterol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1016\/S0140-6736(72)92266-0","article-title":"Gallstone dissolution in man using chenodeoxycholic acid","volume":"2","author":"Bell","year":"1972","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"12570","DOI":"10.1128\/JVI.05839-11","article-title":"Inhibitory effects of bile acids and synthetic farnesoid x receptor agonists on rotavirus replication","volume":"85","author":"Kim","year":"2011","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3273","DOI":"10.1128\/JVI.03478-13","article-title":"Viral entry of hepatitis b and d viruses and bile salts transportation share common molecular determinants on sodium taurocholate cotransporting polypeptide","volume":"88","author":"Yan","year":"2014","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1007\/s13238-016-0287-0","article-title":"Ribavirin is effective against drug-resistant h7n9 influenza virus infections","volume":"7","author":"Bi","year":"2016","journal-title":"Protein Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.antiviral.2013.09.021","article-title":"Germacrone inhibits early stages of influenza virus infection","volume":"100","author":"Liao","year":"2013","journal-title":"Antiviral Res."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kakisaka, M., Sasaki, Y., Yamada, K., Kondoh, Y., Hikono, H., Osada, H., Tomii, K., Saito, T., and Aida, Y. (2015). A novel antiviral target structure involved in the rna binding, dimerization, and nuclear export functions of the influenza a virus nucleoprotein. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1005062"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Chase, G., Rameix-Welti, M., Zvirbliene, A., Zvirblis, G., G\u00f6tz, V., Wolff, T., Naffakh, N., and Schwemmle, M. (2011). Influenza virus ribonucleoprotein complexes gain preferential access to cellular export machinery through chromatin targeting. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1002187"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/0092-8674(91)90576-K","article-title":"Nuclear transport of influenza virus ribonucleoproteins: The viral matrix protein (M1) promotes export and inhibits import","volume":"67","author":"Martin","year":"1991","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/0962-8924(96)81017-8","article-title":"The role of nuclear import and export in influenza virus infection","volume":"6","author":"Whittaker","year":"1996","journal-title":"Trends Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1111\/cmi.12343","article-title":"Influenza virus replication in lung epithelial cells depends on redox-sensitive pathways activated by NOX4-derived ROS","volume":"17","author":"Donatella","year":"2015","journal-title":"Cell. Microbiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1128\/JVI.74.4.1781-1786.2000","article-title":"Role of the Influenza Virus M1 Protein in Nuclear Export of Viral Ribonucleoproteins","volume":"74","author":"Bui","year":"2000","journal-title":"J. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6751","DOI":"10.1093\/emboj\/19.24.6751","article-title":"Influenza A virus NS2 protein mediates vRNP nuclear export through NES-independent interaction with hCRM1","volume":"19","author":"Neumann","year":"2000","journal-title":"EMBO J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"30931","DOI":"10.1074\/jbc.M403258200","article-title":"NF-\u03baB-dependent Induction of Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) and Fas\/FasL Is Crucial for Efficient Influenza Virus Propagation","volume":"279","author":"Wurzer","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1083\/jcb.151.5.951","article-title":"Caspases Disrupt the Nuclear-Cytoplasmic Barrier","volume":"151","author":"Faleiro","year":"2000","journal-title":"J. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2717","DOI":"10.1093\/emboj\/cdg279","article-title":"Caspase 3 activation is essential for efficient influenza virus propagation","volume":"22","author":"Wurzer","year":"2003","journal-title":"EMBO J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5821","DOI":"10.3892\/mmr.2015.4159","article-title":"Activated farnesoid X receptor attenuates apoptosis and liver injury in autoimmune hepatitis","volume":"12","author":"Lian","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1111\/j.1440-1746.2006.04363.x","article-title":"Chenodeoxycholic acid and taurochenodexycholic acid induce anti-apoptotic cIAP-1 expression in human hepatocytes","volume":"21","author":"Hirano","year":"2006","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Huo, C., Xiao, K., Zhang, S., Tang, Y., Wang, M., Qi, P., and Hu, Y. (2018). H5N1 Influenza a Virus Replicates Productively in Pancreatic Cells and Induces Apoptosis and Pro-Inflammatory Cytokine Response. Front Cell Infect Microbiol., 8.","DOI":"10.3389\/fcimb.2018.00386"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"42541","DOI":"10.18632\/oncotarget.6448","article-title":"Saikosaponin a inhibits influenza a virus replication and lung immunopathology","volume":"6","author":"Chen","year":"2015","journal-title":"Oncotarget"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1128\/JCM.42.2.759-763.2004","article-title":"Comparison of Sensitivities of Virus Isolation, Antigen Detection, and Nucleic Acid Amplification for Detection of Equine Influenza Virus","volume":"42","author":"Quinlivan","year":"2004","journal-title":"J. Clin. Microbiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1128\/AAC.45.3.743-748.2001","article-title":"Cyclopentane neuraminidase inhibitors with potent in vitro anti-influenza virus activities","volume":"45","author":"Smee","year":"2001","journal-title":"J. Antimicrob. Chemother."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/12\/3315\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:33:53Z","timestamp":1760196833000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/12\/3315"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,14]]},"references-count":34,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["molecules23123315"],"URL":"https:\/\/doi.org\/10.3390\/molecules23123315","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,12,14]]}}}