Intracellular SCARB2 mimicry overcomes decoy failure to broadly inhibit enteroviruses
5 affiliations
- 1Cancer Centre, The First Hospital of Jilin University, Changchun, Jilin, China.
- 2Institute of Virology and AIDS Research, The First Hospital of Jilin University, Changchun, Jilin, China.
- 3Department of Respiration, Children's Medical Center, First Hospital, Jilin University, Changchun, Jilin, China.
- 4Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ZhejiangChina.
- 5Institute of Translational Medicine, Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, Jilin, China.
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.
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BibTeX
@article{wang2026intracellular,
title = {{Intracellular SCARB2 mimicry overcomes decoy failure to broadly inhibit enteroviruses}},
author = {Shijin Wang and Yubin Tang and Songyang Lai and Jiaxin Yang and Qingran Yang and Xize Liu and Xiao-Fang Yu and Haoran Guo and Wei Wei},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014699},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014699},
note = {CC BY},
}
RIS
TY - JOUR
TI - Intracellular SCARB2 mimicry overcomes decoy failure to broadly inhibit enteroviruses
AU - Shijin Wang
AU - Yubin Tang
AU - Songyang Lai
AU - Jiaxin Yang
AU - Qingran Yang
AU - Xize Liu
AU - Xiao-Fang Yu
AU - Haoran Guo
AU - Wei Wei
PY - 2026
DA - 2026/10/13
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014699
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014699
AB - 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.
SN - 1553-7374
SN - 1553-7366
ER -