{ "abstract": "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 (EC50 = 0.156 μg/mL), outstanding safety (selectivity index > 2003), 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 in vivo. 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. Author summary: Hand, foot, and mouth disease (HFMD) caused by EV-A71 and CV-A16 affects millions of children globally each year, but no targeted antiviral drugs exist. Although SCARB2 has long been known as the key uncoating receptor for these pathogens, extracellular soluble SCARB2 decoy strategies have uniformly failed to block infection. In this study, we solved this puzzle by delivering a tiny SCARB2 fragment inside cells instead of keeping it outside. The resulting peptide, RMP(R8), is highly potent, safe, soluble in water, and protects mice from lethal enterovirus infection. Importantly, this work establishes a new antiviral paradigm: for viruses that use receptors inside cells to invade, intracellular receptor mimicry works where traditional extracellular approaches fail. RMP(R8) offers a translatable drug candidate to treat severe HFMD, and our strategy can be adapted to fight many other hard-to-target viral pathogens.", "abstract_shown": true, "affiliations": [ "Cancer Centre, The First Hospital of Jilin University, Changchun, Jilin, China.", "Institute of Virology and AIDS Research, The First Hospital of Jilin University, Changchun, Jilin, China.", "Department of Respiration, Children's Medical Center, First Hospital, Jilin University, Changchun, Jilin, China.", "Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ZhejiangChina.", "Institute of Translational Medicine, Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin, China." ], "article_type": "Research Article", "arxiv": null, "author_total": 9, "authors": [ { "affs": [ 0, 1 ], "name": "Shijin Wang" }, { "affs": [ 0, 1 ], "name": "Yubin Tang" }, { "affs": [ 1 ], "name": "Songyang Lai" }, { "affs": [ 1 ], "name": "Jiaxin Yang" }, { "affs": [ 0, 2 ], "name": "Qingran Yang" }, { "affs": [ 0 ], "name": "Xize Liu" }, { "affs": [ 3 ], "name": "Xiao-Fang Yu" }, { "affs": [ 0, 1 ], "name": "Haoran Guo" }, { "affs": [ 0, 1, 4 ], "name": "Wei Wei", "orcid": "0000-0003-4456-840X" } ], "bibtex": "https://research.draconitic.com/paper/av7pzk8ezy0b7.bib", "cited_by": 0, "doi": "10.1371/journal.ppat.1014699", "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014699", "id": "av7pzk8ezy0b7", "issns": [ "1553-7374", "1553-7366" ], "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014699", "language": "eng", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2705|Viral Infections and Immunology Research" ], [ "plos", "/Biology and life sciences/Anatomy/Musculoskeletal system/Muscles/Cardiac muscles" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Intracellular receptors" ], [ "plos", "/Biology and life sciences/Cell biology/Signal transduction/Intracellular receptors" ], [ "plos", "/Biology and life sciences/Immunology/Vaccination and immunization/Antiviral therapy" ], [ "plos", "/Biology and life sciences/Microbiology/Virology/Viral replication" ], [ "plos", "/Biology and life sciences/Microbiology/Virology/Viral structure/Virions" ], [ "plos", "/Medicine and health sciences/Anatomy/Musculoskeletal system/Muscles/Cardiac muscles" ], [ "plos", "/Medicine and health sciences/Immunology/Vaccination and immunization/Antiviral therapy" ], [ "plos", "/Medicine and health sciences/Medical conditions/Infectious diseases/Viral diseases/Enterovirus infection" ], [ "plos", "/Medicine and health sciences/Medical conditions/Infectious diseases/Viral diseases/Hand, foot and mouth disease" ], [ "plos", "/Medicine and health sciences/Public and occupational health/Preventive medicine/Vaccination and immunization/Antiviral therapy" ], [ "plos", "/Research and analysis methods/Animal studies/Experimental organism systems/Animal models/Mouse models" ], [ "plos", "/Research and analysis methods/Animal studies/Experimental organism systems/Model organisms/Mouse models" ], [ "plos", "/Research and analysis methods/Model organisms/Mouse models" ] ], "openalex": "W7221611333", "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014699&type=printable", "pmcid": "PMC13705605", "pmid": "42868179", "published": "2026-10-13", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/av7pzk8ezy0b7.ris", "sources": [ { "first_seen": "2026-10-30T12:17:30Z", "native_id": "10.1371/journal.ppat.1014699", "source": "plos", "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014699" }, { "first_seen": "2026-10-30T12:19:00Z", "native_id": "MED:42868179", "source": "europepmc", "url": "https://europepmc.org/article/MED/42868179" } ], "subjects": [ { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" }, { "field": "biology", "origin": "plos:virology", "subfield": "microbiology" }, { "field": "medicine", "origin": "plos:anatomy", "subfield": "physiology" } ], "title": "Intracellular SCARB2 mimicry overcomes decoy failure to broadly inhibit enteroviruses", "title_text": "Intracellular SCARB2 mimicry overcomes decoy failure to broadly inhibit enteroviruses", "type": "peer-reviewed", "updated_at": "2026-10-30T12:19:00Z", "url": "https://research.draconitic.com/paper/av7pzk8ezy0b7", "venue": "PLOS Pathogens", "versions": [] }