Discovery and structural characterization of a therapeutic antibody against coxsackievirus A10

Zhu, Rui; Xu, Longfa; Zheng, Qingbing; Cui, Yanxiang; Li, Shaowei; He, Maozhou; Yin, Zhichao; Liu, Dongxiao; Li, Shuxuan; Li, Zizhen; Chen, Zhenqin; Yu, Hai; Que, Yuqiong; Kong, Zhibo; Zhang, Jun; Baker, Timothy S.; Yan, Xiaodong; Zh, Zhou; Cheng, Tong; Xia, Ningshao

doi:10.1126/sciadv.aat7459

Cited by 20 publications

(29 citation statements)

References 62 publications

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“…This contributes to a distinct electrostatic surface potential compared to HFMD viruses from other receptor sub-groups. In these and all other respects CV-A10 Kowalik is closely similar to previously determined CV-A10 structures 14,23,24 (RMSDs in Cαs for superimposed polypeptides is 0.6-0.8 Å). Differences between strains are confined to the flexible surface loops suggestive of antigenic variation between them.…”

Section: Resultssupporting

confidence: 83%

“…Structure of the mature CV-A10 capsid. CV-A10 Kowalik shares~94% identity to those strains of CV-A10 for which structures are available (strain FJ-01 PDB ID: 6ACU, strain S0148b PDB ID: 6IIJ and strain SJZ10-1740T/HeB/CHN/2010 PDB ID: 6AKU) 14,23,24 , which themselves share 98% identity. As expected, the structure of CV-A10 Kowalik maintains the typical enterovirus architecture and surface topography but a signature of CV-A10 viruses is an extended VP1 BC loop that, together with the absence of helical structure in the VP1 GH loop, widens the front part of the canyon whilst the extended VP2 EF loop is bent inwards narrowing the rear of the canyon and the VP3 Cterminus protrudes into the base of the canyon.…”

Section: Resultsmentioning

confidence: 99%

“…Differences between strains are confined to the flexible surface loops suggestive of antigenic variation between them. The hydrophobic pocket within the VP1 β-barrel contains a bound aliphatic chain that has been modelled as sphingosine in accordance with other CV-A10 strains 14,23,24 . The density level for this molecule is lower than the adjacent capsid protein, suggesting an occupancy of circa 50% (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Two known antibodies act by blocking receptor binding. Two structures of complexes of KRM1-dependent viruses with neutralizing antibody Fabs are known, CV-A6/1D5 30 and CV-A10/ 2G8 24 . 2G8 binds on a plateau south of the canyon at the VP2/ VP3 boundary, interacting with the C-termini of VP1 and VP3, the EF loop of VP2 and residues preceding the B strand of VP3, whilst five 1D5 Fabs bind around the fivefold vertex, interacting with the BC, DE, EF and HI loops of VP1.…”

Section: Resultsmentioning

confidence: 99%

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Hand-foot-and-mouth disease virus receptor KREMEN1 binds the canyon of Coxsackie Virus A10

et al. 2020

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Coxsackievirus A10 (CV-A10) is responsible for an escalating number of severe infections in children, but no prophylactics or therapeutics are currently available. KREMEN1 (KRM1) is the entry receptor for the largest receptor-group of hand-foot-and-mouth disease causing viruses, which includes CV-A10. We report here structures of CV-A10 mature virus alone and in complex with KRM1 as well as of the CV-A10 A-particle. The receptor spans the viral canyon with a large footprint on the virus surface. The footprint has some overlap with that seen for the neonatal Fc receptor complexed with enterovirus E6 but is larger and distinct from that of another enterovirus receptor SCARB2. Reduced occupancy of a particle-stabilising pocket factor in the complexed virus and the presence of both unbound and expanded virus particles suggests receptor binding initiates a cascade of conformational changes that produces expanded particles primed for viral uncoating.

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Section: Resultssupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Hand-foot-and-mouth disease virus receptor KREMEN1 binds the canyon of Coxsackie Virus A10

et al. 2020

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“…E30-4B10 E3-6C5 E3-4B10 E11-6C5 E11-4B10 CVB3-6C5 CVB3-4B10 E6-6C5 E6-4B10 250.00 nM 125.00 nM 62. 50 A n ti-F -p a r se ra A n ti-E -p a r se ra A n ti-a d j se ra f Titration of sera from mice immunized with E30 F-particle or E-particle. Both antisera could highly neutralize E30, while the sera from adjuvant-immunized mice failed to protect RD cells from E30 infection.…”

Section: Resultsmentioning

confidence: 99%

Serotype specific epitopes identified by neutralizing antibodies underpin immunogenic differences in Enterovirus B

et al. 2020

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Echovirus 30 (E30), a serotype of Enterovirus B (EV-B), recently emerged as a major causative agent of aseptic meningitis worldwide. E30 is particularly devastating in the neonatal population and currently no vaccine or antiviral therapy is available. Here we characterize two highly potent E30-specific monoclonal antibodies, 6C5 and 4B10, which efficiently block binding of the virus to its attachment receptor CD55 and uncoating receptor FcRn. Combinations of 6C5 and 4B10 augment the sum of their individual anti-viral activities. Highresolution structures of E30-6C5-Fab and E30-4B10-Fab define the location and nature of epitopes targeted by the antibodies. 6C5 and 4B10 engage the capsid loci at the north rim of the canyon and in-canyon, respectively. Notably, these regions exhibit antigenic variability across EV-Bs, highlighting challenges in development of broad-spectrum antibodies. Our structures of these neutralizing antibodies of E30 are instructive for development of vaccines and therapeutics against EV-B infections.

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Development of an efficient neutralization assay for Coxsackievirus A10

Liu

Zhu

et al. 2019

Appl Microbiol Biotechnol

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Coxsackievirus A10 (CVA10) recently has become one of the major pathogens of hand, foot, and mouth disease (HFMD) in children worldwide, but no cure or vaccine against CVA10 is available yet. Serological evaluation of herd immunity to CVA10 will promote the development of vaccine. The traditional neutralization assay based on inhibition of cytopathic effect (Nt-CPE) is a common method for measuring neutralizing antibody titer against CVA10, which is time-consuming and labor-intensive. In this study, an efficient neutralization test based on a monoclonal antibody (mAb) 3D1 against CVA10, called Elispot-based neutralization test (Nt-Elispot), was developed. In the Nt-Elispot, the mAb 3D1 labeled with horseradish peroxidase (HRP) was used to detect the CVA10-infected RD cells at a 1:4000 dilution and the optimal infectious dose of CVA10 was set at 10 5 TCID 50 /well when combined with a fixed incubation time of 14 h. Compared with the Nt-CPE, the Nt-Elispot method effectively shortened the detection period and presented a good correlativity with it. Using the Nt-Elispot, a total of 123 sera from healthy children were tested for neutralizing antibody against CVA10, demonstrating that the overall seroprevalence was 49.3% (54/123) and the geometric mean titer (GMT) had been calculated as 574.2. Furthermore, 2 anti-CVA10 neutralizing mAbs were obtained by screening via the Nt-Elispot. Overall, the established Nt-Elispot could be used as an efficient and high-throughput method for evaluating immunity to CVA10 and screening the neutralizing antibodies.

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Discovery and structural characterization of a therapeutic antibody against coxsackievirus A10

Abstract: Isolation of the first neutralizing antibody of CVA10 and the mechanism underlying its potency against all three existing capsid forms.

Cited by 20 publications

References 62 publications

Hand-foot-and-mouth disease virus receptor KREMEN1 binds the canyon of Coxsackie Virus A10

Hand-foot-and-mouth disease virus receptor KREMEN1 binds the canyon of Coxsackie Virus A10

Serotype specific epitopes identified by neutralizing antibodies underpin immunogenic differences in Enterovirus B

Development of an efficient neutralization assay for Coxsackievirus A10

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