{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T18:44:44Z","timestamp":1791917084467,"version":"4.3.4"},"reference-count":34,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:00:00Z","timestamp":1791849600000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Prevention and Control of Emerging and Major Infectious Diseases-National Science and Technology Major Project","award":["2025ZD01903702"],"award-info":[{"award-number":["2025ZD01903702"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Enterovirus A71 (EV-A71) and coxsackievirus A16 (CV-A16) are leading causes of severe hand, foot, and mouth disease (HFMD) with high childhood mortality and no specific antiviral therapy. SCARB2 is the essential uncoating receptor, yet extracellular SCARB2-Fc decoys fail to block infection, representing a decade-old paradox in enterovirus therapeutics. Here, we overcome this limitation by engineering RMP(R8), a cell-penetrating SCARB2 mimetic peptide comprising the minimal VP2-binding domain (W146-K166) fused to an octa-arginine transporter. RMP(R8) shows potent antiviral activity (EC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u20090.156 \u03bcg\/mL), outstanding safety (selectivity index\u2009&gt;\u20092003), and excellent aqueous solubility, a critical asset for clinical translation. It broadly inhibits genetically divergent EV-A71 isolates and CV-A16 in intestinal and neural cells by blocking viral entry. In a lethal neonatal mouse model, RMP(R8) increases survival against EV-A71 and CV-A16 challenge\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Intracellular receptor mimicry thus establishes a generalizable strategy for viruses refractory to extracellular intervention. RMP(R8) is a promising clinical candidate to address the unmet need for targeted anti-enterovirus treatment, and our findings redefine how to drug virus-receptor interactions that act inside cells.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014699","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T17:46:57Z","timestamp":1791913617000},"page":"e1014699","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intracellular SCARB2 mimicry overcomes decoy failure to broadly inhibit enteroviruses"],"prefix":"10.1371","volume":"22","author":[{"given":"Shijin","family":"Wang","sequence":"first","affiliation":[{"name":"The First Hospital of Jilin University","place":["Changchun, Jilin, China"],"department":["Cancer Centre"]},{"name":"The First Hospital of Jilin University","place":["Changchun, Jilin, China"],"department":["Institute of Virology and AIDS Research"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubin","family":"Tang","sequence":"additional","affiliation":[{"name":"The First Hospital of Jilin University","place":["Changchun, Jilin, China"],"department":["Cancer Centre"]},{"name":"The First Hospital of Jilin University","place":["Changchun, Jilin, China"],"department":["Institute of Virology and AIDS Research"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songyang","family":"Lai","sequence":"additional","affiliation":[{"name":"The First Hospital of Jilin University","place":["Changchun, Jilin, China"],"department":["Institute of Virology and AIDS Research"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxin","family":"Yang","sequence":"additional","affiliation":[{"name":"The First Hospital of Jilin University","place":["Changchun, Jilin, China"],"department":["Institute of Virology and AIDS Research"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingran","family":"Yang","sequence":"additional","affiliation":[{"name":"The First Hospital of Jilin University","place":["Changchun, Jilin, China"],"department":["Cancer Centre"]},{"name":"Jilin University","place":["Changchun, Jilin, China"],"department":["Department of Respiration, Children\u2019s Medical Center, First Hospital"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xize","family":"Liu","sequence":"additional","affiliation":[{"name":"The First Hospital of Jilin University","place":["Changchun, Jilin, China"],"department":["Cancer Centre"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Fang","family":"Yu","sequence":"additional","affiliation":[{"name":"Zhejiang University School of Medicine","place":["Hangzhou, Zhejiang, China"],"department":["Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoran","family":"Guo","sequence":"additional","affiliation":[{"name":"The First Hospital of Jilin University","place":["Changchun, Jilin, China"],"department":["Cancer Centre"]},{"name":"The First Hospital of Jilin University","place":["Changchun, Jilin, China"],"department":["Institute of Virology and AIDS Research"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4456-840X","authenticated-orcid":true,"given":"Wei","family":"Wei","sequence":"additional","affiliation":[{"name":"The First Hospital of Jilin University","place":["Changchun, Jilin, China"],"department":["Cancer Centre"]},{"name":"The First Hospital of Jilin University","place":["Changchun, Jilin, China"],"department":["Institute of Virology and AIDS Research"]},{"name":"The First Hospital of Jilin University","place":["Changchun, Jilin, China"],"department":["Institute of Translational Medicine, Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,10,13]]},"reference":[{"issue":"11","key":"ppat.1014699.ref001","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1016\/S1473-3099(10)70194-8","article-title":"Virology, epidemiology, pathogenesis, and control of enterovirus 71","volume":"10","author":"T Solomon","year":"2010","journal-title":"Lancet Infect Dis"},{"issue":"9","key":"ppat.1014699.ref002","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1056\/NEJMoa1303224","article-title":"An inactivated enterovirus 71 vaccine in healthy children","volume":"370","author":"R Li","year":"2014","journal-title":"N Engl J Med"},{"issue":"9","key":"ppat.1014699.ref003","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1056\/NEJMoa1304923","article-title":"Efficacy, safety, and immunogenicity of an enterovirus 71 vaccine in China","volume":"370","author":"F Zhu","year":"2014","journal-title":"N Engl J Med"},{"issue":"13","key":"ppat.1014699.ref004","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1056\/NEJM199909233411302","article-title":"Neurologic complications in children with enterovirus 71 infection","volume":"341","author":"CC Huang","year":"1999","journal-title":"N Engl J Med"},{"issue":"11","key":"ppat.1014699.ref005","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1016\/S1474-4422(10)70209-X","article-title":"Clinical features, diagnosis, and management of enterovirus 71","volume":"9","author":"MH Ooi","year":"2010","journal-title":"Lancet Neurol"},{"issue":"2","key":"ppat.1014699.ref006","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1128\/AAC.00942-08","article-title":"Safety, pharmacokinetics, and antiretroviral activity of multiple doses of ibalizumab (formerly TNX-355), an anti-CD4 monoclonal antibody, in human immunodeficiency virus type 1-infected adults","volume":"53","author":"JM Jacobson","year":"2009","journal-title":"Antimicrob Agents Chemother"},{"issue":"5996","key":"ppat.1014699.ref007","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1038\/312763a0","article-title":"The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus","volume":"312","author":"AG Dalgleish","year":"1984","journal-title":"Nature"},{"issue":"14","key":"ppat.1014699.ref008","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1056\/NEJMoa0803152","article-title":"Maraviroc for previously treated patients with R5 HIV-1 infection","volume":"359","author":"RM Gulick","year":"2008","journal-title":"N Engl J Med"},{"issue":"7","key":"ppat.1014699.ref009","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1038\/nm.1992","article-title":"Scavenger receptor B2 is a cellular receptor for enterovirus 71","volume":"15","author":"S Yamayoshi","year":"2009","journal-title":"Nat 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(Lond)"},{"issue":"10","key":"ppat.1014699.ref013","doi-asserted-by":"crossref","first-page":"5686","DOI":"10.1128\/JVI.00020-12","article-title":"Human SCARB2-dependent infection by coxsackievirus A7, A14, and A16 and enterovirus 71","volume":"86","author":"S Yamayoshi","year":"2012","journal-title":"J Virol"},{"issue":"2","key":"ppat.1014699.ref014","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1012022","article-title":"Enterovirus A71 does not meet the uncoating receptor SCARB2 at the cell surface","volume":"20","author":"Y Nishimura","year":"2024","journal-title":"PLoS Pathog"},{"issue":"3","key":"ppat.1014699.ref015","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1038\/s41564-018-0319-z","article-title":"Unexpected mode of engagement between enterovirus 71 and its receptor SCARB2","volume":"4","author":"D Zhou","year":"2019","journal-title":"Nat 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Zhu","year":"2026","journal-title":"Viruses"},{"issue":"7","key":"ppat.1014699.ref030","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1003511","article-title":"Enterovirus 71 binding to PSGL-1 on leukocytes: VP1-145 acts as a molecular switch to control receptor interaction","volume":"9","author":"Y Nishimura","year":"2013","journal-title":"PLoS Pathog"},{"issue":"10","key":"ppat.1014699.ref031","article-title":"VP2 residue N142 of coxsackievirus A10 is critical for the interaction with KREMEN1 receptor and neutralizing antibodies and the pathogenicity in mice","volume":"19","author":"X Li","year":"2023","journal-title":"PLoS Pathog"},{"issue":"5996","key":"ppat.1014699.ref032","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/312767a0","article-title":"T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV","volume":"312","author":"D Klatzmann","year":"1984","journal-title":"Nature"},{"issue":"2","key":"ppat.1014699.ref033","article-title":"Enterovirus D68 receptor usage: from static attachment to dynamic entry","volume":"100","author":"D Liu","year":"2026","journal-title":"J Virol"},{"issue":"7","key":"ppat.1014699.ref034","article-title":"Coxsackievirus A16 utilizes cell surface heparan sulfate glycosaminoglycans as its attachment receptor","volume":"6","author":"X Zhang","year":"2017","journal-title":"Emerg Microbes Infect"}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1014699","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T17:47:05Z","timestamp":1791913625000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1014699"}},"subtitle":[],"editor":[{"given":"Peter","family":"Sarnow","sequence":"first","affiliation":[{"name":"Stanford University","place":["UNITED STATES OF AMERICA"]}],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,10,13]]},"references-count":34,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,10,13]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1014699","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,13]]}}}