Cao, Lei and Liu, Pi and Yang, Pan and Gao, Qiang and Li, Hong and Sun, Yao and Zhu, Ling and Lin, Jianping and Su, Dan and Rao, Zihe and Wang, Xiangxi and Kwong, Peter D. (2019) Structural basis for neutralization of hepatitis A virus informs a rational design of highly potent inhibitors. PLOS Biology, 17 (4). e3000229. ISSN 1545-7885
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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.
Item Type: | Article |
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Subjects: | GO STM Archive > Biological Science |
Divisions: | Faculty of Engineering, Science and Mathematics > School of Chemistry |
Depositing User: | Unnamed user with email support@gostmarchive.com |
Date Deposited: | 12 Jan 2023 11:57 |
Last Modified: | 01 Jul 2024 11:19 |
URI: | http://journal.openarchivescholar.com/id/eprint/49 |