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Particularly, enterovirus-A71 (EV-A71), the main pathogen causing hand-foot-and-mouth disease (HFMD), has caused ongoing outbreaks globally in recent years associated with severe neurological manifestations and several deaths. Currently, no effective antivirals are available for the prevention or treatment of EV-A71 infection. In this study, we found that sodium copper chlorophyllin (CHL), a health food additive and an over-the-counter anticancer medicine or treatment to reduce the odor of urine or feces, exhibited potent inhibitory activity against infection by divergent EV-A71 and coxsackievirus-A16 (CV-A16) isolates at a low micromolar concentration with excellent safety. The antiviral activity of each was confirmed by colorimetric viral infection and qRT-PCR assays. A series of mechanistic studies showed that CHL did not target the host cell but blocked the entry of EV-A71 and CV-A16 into the host cell at the postattachment stage. In the mouse model, CHL could significantly reduce the viral titer in the lungs and muscles. Since CHL has been used in clinics for many years with excellent safety, it has the potential to be further developed into a prophylactic or therapeutic to prevent or treat HFMD caused by EV-A71 or CV-A16 infection.<\/jats:p>","DOI":"10.1021\/acsinfecdis.0c00096","type":"journal-article","created":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T14:12:56Z","timestamp":1585750376000},"page":"882-890","source":"Crossref","is-referenced-by-count":24,"title":["Sodium Copper Chlorophyllin Is Highly Effective against\nEnterovirus (EV) A71 Infection by Blocking Its Entry into the Host\nCell"],"prefix":"10.1021","volume":"6","author":[{"given":"Zezhong","family":"Liu","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences, Fudan University , , ,","place":["Shanghai, China, 200032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Xia","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fudan University , , ,","place":["Shanghai, China, 200032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinling","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fudan University , , ,","place":["Shanghai, China, 200032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaoshuai","family":"Lan","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fudan University , , ,","place":["Shanghai, China, 200032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyu","family":"Li","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fudan University , , ,","place":["Shanghai, China, 200032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fudan University , , ,","place":["Shanghai, China, 200032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fudan University , , ,","place":["Shanghai, China, 200032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Lu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fudan University , , ,","place":["Shanghai, China, 200032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8283-7135","authenticated-orcid":true,"given":"Shibo","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Fudan University , , ,","place":["Shanghai, China, 200032"]},{"name":"New York Blood Center , , , ,","place":["New York, New York, United\nStates, 10065"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,4,1]]},"reference":[{"key":"2026081806114332800_cit1","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1038\/s41579-018-0005-4","article-title":"The\nlife cycle of non-polio enteroviruses and how to target it","volume":"16","author":"Baggen","year":"2018","journal-title":"Nat. Rev. Microbiol."},{"key":"2026081806114332800_cit2","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1186\/s12929-019-0573-2","article-title":"The History\nof Enterovirus A71 Outbreaks and Molecular Epidemiology in the Asia-Pacific\nRegion","volume":"26","author":"Puenpa","year":"2019","journal-title":"J. Biomed. Sci."},{"key":"2026081806114332800_cit3","doi-asserted-by":"publisher","first-page":"20632","DOI":"10.3402\/ehtj.v6i0.20632","article-title":"What we are watching--five\ntop global infectious disease threats, 2012: a perspective from CDC\u2019s\nGlobal Disease Detection Operations Center","volume":"6","author":"Christian","year":"2013","journal-title":"Emerg Health Threats J."},{"key":"2026081806114332800_cit4","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1007\/s12250-015-3573-8","article-title":"Monoclonal neutralizing antibodies\nagainst EV71 screened from mice immunized with yeast-produced virus-like\nparticles","volume":"30","author":"Lin","year":"2015","journal-title":"Virol. Sin."},{"key":"2026081806114332800_cit5","doi-asserted-by":"publisher","first-page":"4","DOI":"10.7774\/cevr.2017.6.1.4","article-title":"Enterovirus\n71 infection and vaccines","volume":"6","author":"Yi","year":"2017","journal-title":"Clin. Exp. Vaccine\nRes."},{"key":"2026081806114332800_cit6","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1016\/S1473-3099(13)70342-6","article-title":"Hand, foot,\nand mouth disease in\nChina, 2008\u201312: an epidemiological study","volume":"14","author":"Xing","year":"2014","journal-title":"Lancet Infect. Dis."},{"key":"2026081806114332800_cit7","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1007\/s12250-018-0071-9","article-title":"Recent Progress on Functional Genomics\nResearch of Enterovirus 71","volume":"34","author":"Wang","year":"2019","journal-title":"Virol. Sin."},{"key":"2026081806114332800_cit8","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1016\/S1473-3099(10)70194-8","article-title":"Virology,\nepidemiology, pathogenesis, and control of\nenterovirus 71","volume":"10","author":"Solomon","year":"2010","journal-title":"Lancet Infect. Dis."},{"key":"2026081806114332800_cit9","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1086\/314032","article-title":"Deaths of children\nduring an outbreak of hand, foot, and mouth disease in Sarawak, Malaysia:\nClinical and pathological characteristics of the disease","volume":"31","author":"Chan","year":"2000","journal-title":"Clin. Infect. Dis."},{"key":"2026081806114332800_cit10","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1056\/NEJM199909233411301","article-title":"An epidemic of enterovirus\n71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group","volume":"341","author":"Ho","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"2026081806114332800_cit11","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1086\/520149","article-title":"Clinical\nspectrum of enterovirus 71 infection in children in southern Taiwan,\nwith an emphasis on neurological complications","volume":"29","author":"Wang","year":"1999","journal-title":"Clin. Infect. Dis."},{"key":"2026081806114332800_cit12","doi-asserted-by":"publisher","first-page":"432","DOI":"10.3201\/eid2403.171303","article-title":"Epidemiology of Recurrent Hand, Foot and Mouth Disease,\nChina, 2008\u20132015","volume":"24","author":"Huang","year":"2018","journal-title":"Emerging Infect. 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Chem."},{"key":"2026081806114332800_cit16","doi-asserted-by":"publisher","first-page":"12084","DOI":"10.1128\/JVI.02189-15","article-title":"Single Neutralizing\nMonoclonal Antibodies Targeting the VP1 GH Loop of Enterovirus 71\nInhibit both Virus Attachment and Internalization during Viral Entry","volume":"89","author":"Ku","year":"2015","journal-title":"J. Virol."},{"key":"2026081806114332800_cit17","doi-asserted-by":"publisher","first-page":"E12209","DOI":"10.1073\/pnas.1803347115","article-title":"Molecular basis for the acid-initiated uncoating of\nhuman enterovirus D68","volume":"115","author":"Liu","year":"2018","journal-title":"Proc. Natl. Acad. Sci.\nU. S. A."},{"key":"2026081806114332800_cit18","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1038\/nsmb.2255","article-title":"A sensor-adaptor mechanism for enterovirus uncoating from structures\nof EV71","volume":"19","author":"Wang","year":"2012","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2026081806114332800_cit19","doi-asserted-by":"publisher","first-page":"4985","DOI":"10.1038\/s41467-018-07531-0","article-title":"Structures\nof Coxsackievirus A10 unveil the molecular mechanisms of receptor\nbinding and viral uncoating","volume":"9","author":"Zhu","year":"2018","journal-title":"Nat. Commun."},{"key":"2026081806114332800_cit20","doi-asserted-by":"publisher","first-page":"6990","DOI":"10.1128\/AAC.03328-14","article-title":"The capsid\nbinder Vapendavir\nand the novel protease inhibitor SG85 inhibit enterovirus 71 replication","volume":"58","author":"Tijsma","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026081806114332800_cit21","doi-asserted-by":"publisher","first-page":"1644","DOI":"10.1021\/jm010536a","article-title":"Design,\nsynthesis, and structure-activity\nrelationship of pyridyl imidazolidinones: a novel class of potent\nand selective human enterovirus 71 inhibitors","volume":"45","author":"Shia","year":"2002","journal-title":"J. Med. Chem."},{"key":"2026081806114332800_cit22","doi-asserted-by":"publisher","first-page":"7779","DOI":"10.1128\/AAC.00766-15","article-title":"In Vitro Efficacy\nof Antiviral Compounds against Enterovirus D68","volume":"59","author":"Rhoden","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026081806114332800_cit23","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1016\/j.antiviral.2012.12.029","article-title":"Rupintrivir is a promising candidate for treating severe\ncases of enterovirus-71 infection: evaluation of antiviral efficacy\nin a murine infection model","volume":"97","author":"Zhang","year":"2013","journal-title":"Antiviral Res."},{"key":"2026081806114332800_cit24","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1126\/science.1261962","article-title":"Structure\nand inhibition of EV-D68, a virus that causes respiratory illness\nin children","volume":"347","author":"Liu","year":"2015","journal-title":"Science"},{"key":"2026081806114332800_cit25","doi-asserted-by":"publisher","first-page":"e64","DOI":"10.1016\/S1473-3099(15)00543-5","article-title":"Global\nemergence of enterovirus D68:\na systematic review","volume":"16","author":"Holm-Hansen","year":"2016","journal-title":"Lancet Infect. Dis."},{"key":"2026081806114332800_cit26","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1021\/ml2002955","article-title":"An Orally\nAvailable 3-Ethoxybenzisoxazole Capsid Binder with Clinical Activity\nagainst Human Rhinovirus","volume":"3","author":"Feil","year":"2012","journal-title":"ACS Med. Chem. Lett."},{"key":"2026081806114332800_cit27","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1016\/j.ejmech.2019.06.008","article-title":"Back to the future:\nAdvances in development of broad-spectrum capsid-binding inhibitors\nof enteroviruses","volume":"178","author":"Egorova","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"2026081806114332800_cit28","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1080\/01635581.2015.990573","article-title":"Chemopreventive\npotential of chlorophyllin:\na review of the mechanisms of action and molecular targets","volume":"67","author":"Nagini","year":"2015","journal-title":"Nutr. Cancer"},{"key":"2026081806114332800_cit29","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1016\/j.foodres.2011.10.031","article-title":"Copper chlorophyllin: A food colorant\nwith bioactive\nproperties?","volume":"46","author":"Tumolo","year":"2012","journal-title":"Food Res. Int."},{"key":"2026081806114332800_cit30","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.bbagen.2004.03.002","article-title":"Effect\nof chlorophyllin against oxidative\nstress in splenic lymphocytes in vitro and in vivo","volume":"1672","author":"Kumar","year":"2004","journal-title":"Biochim. Biophys. Acta, Gen. Subj."},{"key":"2026081806114332800_cit31","doi-asserted-by":"publisher","first-page":"6406","DOI":"10.1074\/jbc.M111.301622","article-title":"Molecular\nDeterminants\nof Enterovirus 71 Viral Entry CLEFT AROUND GLN-172 ON VP1 PROTEIN\nINTERACTS WITH VARIABLE REGION ON SCAVENGE RECEPTOR B 2","volume":"287","author":"Chen","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2026081806114332800_cit32","doi-asserted-by":"publisher","first-page":"1952","DOI":"10.1021\/acsinfecdis.9b00284","article-title":"A Novel Capsid Binding\nInhibitor Displays Potent Antiviral Activity against Enterovirus D68","volume":"5","author":"Ma","year":"2019","journal-title":"ACS Infect. Dis."},{"key":"2026081806114332800_cit33","doi-asserted-by":"publisher","first-page":"2121","DOI":"10.1128\/JVI.06103-11","article-title":"A Non-Mouse-Adapted\nEnterovirus 71\n(EV71) Strain Exhibits Neurotropism, Causing Neurological Manifestations\nin a Novel Mouse Model of EV71 Infection","volume":"86","author":"Khong","year":"2012","journal-title":"Journal\nof Virology."},{"key":"2026081806114332800_cit34","doi-asserted-by":"publisher","first-page":"14601","DOI":"10.1073\/pnas.251536898","article-title":"Chlorophyllin intervention reduces aflatoxin-DNA adducts\nin individuals at high risk for liver cancer","volume":"98","author":"Egner","year":"2001","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026081806114332800_cit35","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/j.molimm.2006.02.031","article-title":"Antiapoptotic\nand immunomodulatory\neffects of chlorophyllin","volume":"44","author":"Sharma","year":"2007","journal-title":"Mol. Immunol."},{"key":"2026081806114332800_cit36","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.2174\/1389557516666161004161411","article-title":"Chlorophylls\nand their Derivatives Used in Food Industry\nand Medicine","volume":"17","author":"Solymosi","year":"2017","journal-title":"Mini-Rev. Med. Chem."},{"key":"2026081806114332800_cit37","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.freeradbiomed.2015.04.007","article-title":"Amelioration\nof radiation-induced\nhematopoietic syndrome by an antioxidant chlorophyllin through increased\nstem cell activity and modulation of hematopoiesis","volume":"85","author":"Suryavanshi","year":"2015","journal-title":"Free Radical Biol. Med."},{"key":"2026081806114332800_cit38","doi-asserted-by":"publisher","first-page":"2173","DOI":"10.1021\/jf010869g","article-title":"Sodium\ncopper chlorophyllin: In vitro\ndigestive stability and accumulation by Caco-2 human intestinal cells","volume":"50","author":"Ferruzzi","year":"2002","journal-title":"J. Agric. Food Chem."},{"key":"2026081806114332800_cit39","doi-asserted-by":"publisher","first-page":"15672","DOI":"10.1038\/ncomms15672","article-title":"A peptide-based\nviral inactivator inhibits Zika virus infection in pregnant mice and\nfetuses","volume":"8","author":"Yu","year":"2017","journal-title":"Nat. Commun."}],"container-title":["ACS Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsinfecdis.0c00096","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/6\/5\/882\/12724106\/id0c00096.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/6\/5\/882\/12724106\/id0c00096.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T10:51:50Z","timestamp":1787050310000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article\/6\/5\/882\/1292639\/Sodium-Copper-Chlorophyllin-Is-Highly-Effective"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,1]]},"references-count":39,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,4,1]]},"published-print":{"date-parts":[[2020,5,8]]}},"URL":"https:\/\/doi.org\/10.1021\/acsinfecdis.0c00096","relation":{},"ISSN":["2373-8227"],"issn-type":[{"value":"2373-8227","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,1]]}}}