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PLoS Biol. 2019 Apr 30;17(4):e3000229. doi: 10.1371/journal.pbio.3000229. eCollection 2019 Apr.

Structural basis for neutralization of hepatitis A virus informs a rational design of highly potent inhibitors.

Cao L1,2,3, Liu P4, Yang P1,3, Gao Q5, Li H6, Sun Y1,3, Zhu L1,3, Lin J4, Su D2, Rao Z3,6,7, Wang X1,3.

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CAS Key Laboratory of Infection and Immunity, CAS Centre for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, China.
National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Biodesign Center, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China.
Sinovac Biotech Co., Ltd., Beijing, China.
Tianjin International Biomedical Joint Research Institute, Tianjin, China.
Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing, China.


Hepatitis A virus (HAV), an enigmatic and ancient pathogen, is a major causative agent of acute viral hepatitis worldwide. Although there are effective vaccines, antivirals against HAV infection are still required, especially during fulminant hepatitis outbreaks. A more in-depth understanding of the antigenic characteristics of HAV and the mechanisms of neutralization could aid in the development of rationally designed antiviral drugs targeting HAV. In this paper, 4 new antibodies-F4, F6, F7, and F9-are reported that potently neutralize HAV at 50% neutralizing concentration values (neut50) ranging from 0.1 nM to 0.85 nM. High-resolution cryo-electron microscopy (cryo-EM) structures of HAV bound to F4, F6, F7, and F9, together with results of our previous studies on R10 fragment of antigen binding (Fab)-HAV complex, shed light on the locations and nature of the epitopes recognized by the 5 neutralizing monoclonal antibodies (NAbs). All the epitopes locate within the same patch and are highly conserved. The key structure-activity correlates based on the antigenic sites have been established. Based on the structural data of the single conserved antigenic site and key structure-activity correlates, one promising drug candidate named golvatinib was identified by in silico docking studies. Cell-based antiviral assays confirmed that golvatinib is capable of blocking HAV infection effectively with a 50% inhibitory concentration (IC50) of approximately 1 μM. These results suggest that the single conserved antigenic site from complete HAV capsid is a good antiviral target and that golvatinib could function as a lead compound for anti-HAV drug development.

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