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Updated: Jan 8, 2026
Use of Viral Entry Assays and Molecular Docking Analysis for the Identification of Antiviral Candidates against Coxsackievirus A16
Published on: July 15, 2019
Molecular mechanisms of receptor recognition and antibody neutralization of coxsackievirus A6
Xianliang Ke1, Xue Li2, Zeyu Liu2
1State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China.
Abstract:
Coxsackievirus A6 (CVA6), a major cause of hand, foot, and mouth disease, lacks approved vaccines or drugs. KRM1 is its only known receptor, but its precise role remains unclear. This study investigates CVA6's entry mechanism and antibody neutralization. Cryo-EM shows CVA6 clinical strain HeB primarily exists as mature virions. KRM1 binding within the canyon triggers conversion to uncoating intermediate, defining KRM1 as an uncoating receptor for CVA6. However, KRM1 knockout reduces CVA6 infectivity without affecting attachment. Conversely, disrupting heparan sulfate proteoglycan (HSPG) impairs both viral attachment and infectivity, and CVA6 virions bind heparin directly. These results support a two-receptor entry model for CVA6: HSPG mediates viral attachment, while KRM1 induces uncoating. Additionally, we develop two CVA6-specific protective antibodies (1F4 and 3H7), targeting a new antigenic site near the three-fold axis of the viral capsid. These antibodies sterically block KRM1 binding and function post-attachment, consistent with KRM1's role. The findings elucidate CVA6 entry and offer a basis for antibody interventions.
Insights
Coxsackievirus A6 uses two receptors for entry: heparan sulfate proteoglycan (HSPG) for attachment and KRM1 for uncoating. New antibodies block KRM1 binding, offering a potential intervention for hand, foot, and mouth disease.
Area of Science:
- Virology
- Structural Biology
- Immunology
Background:
- Coxsackievirus A6 (CVA6) causes hand, foot, and mouth disease, with no current vaccines or drugs.
- KRM1 is the sole identified receptor for CVA6, but its function in viral entry is not fully understood.
Purpose of the Study:
- To elucidate the entry mechanism of CVA6.
- To investigate the role of KRM1 and heparan sulfate proteoglycan (HSPG) in CVA6 infection.
- To develop neutralizing antibodies against CVA6.
Main Methods:
- Cryo-electron microscopy (Cryo-EM) to determine viral structure and KRM1 interaction.
- KRM1 knockout and HSPG disruption experiments to assess receptor function.
- Development and characterization of CVA6-specific antibodies.
Main Results:
- Cryo-EM revealed KRM1 binding triggers CVA6 uncoating, identifying KRM1 as an uncoating receptor.
- HSPG mediates CVA6 attachment, while KRM1 facilitates uncoating, supporting a two-receptor entry model.
- Two protective antibodies, 1F4 and 3H7, were developed, targeting a novel antigenic site and blocking KRM1 interaction.
Conclusions:
- CVA6 employs a sequential two-receptor entry pathway involving HSPG and KRM1.
- The developed antibodies neutralize CVA6 by inhibiting KRM1 binding, offering a promising therapeutic strategy.
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