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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.

Author information

1
CAS Key Laboratory of Infection and Immunity, CAS Centre for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
2
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, China.
3
National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
4
Biodesign Center, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China.
5
Sinovac Biotech Co., Ltd., Beijing, China.
6
Tianjin International Biomedical Joint Research Institute, Tianjin, China.
7
Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing, China.

Abstract

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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