The mechanism of poly-galloyl-glucoses preventing Influenza A virus entry into host cells

Hu Ge; Ge Liu; Yang-Fei Xiang; Yu Wang; Chao-Wan Guo; Nan-Hao Chen; Ying-Jun Zhang; Yi-Fei Wang; Kaio Kitazato; Jun Xu

doi:10.1371/journal.pone.0094392

The mechanism of poly-galloyl-glucoses preventing Influenza A virus entry into host cells

PLoS One. 2014 Apr 9;9(4):e94392. doi: 10.1371/journal.pone.0094392. eCollection 2014.

Authors

Hu Ge¹, Ge Liu², Yang-Fei Xiang³, Yu Wang¹, Chao-Wan Guo², Nan-Hao Chen¹, Ying-Jun Zhang⁴, Yi-Fei Wang⁵, Kaio Kitazato², Jun Xu¹

Affiliations

¹ School of Pharmaceutical Sciences & Institute of Human Virology, Sun Yat-Sen University, Guangzhou, China.
² Division of Molecular Pharmacology of Infectious agents, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
³ Division of Biomedicine Research and Development Center, Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China; College of Pharmacy, Jinan University, Guangzhou, China.
⁴ Kunming Institute of Botany, the Chinese Academy of Sciences, Kunming, China.
⁵ Division of Biomedicine Research and Development Center, Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, China.

Abstract

Hemagglutinin (HA) is essential for Influenza A virus infection, but its diversity of subtypes presents an obstacle to developing broad-spectrum HA inhibitors. In this study, we investigated the molecular mechanisms by which poly-galloyl glucose (pGG) analogs inhibit influenza hemagglutinin (HA) in vitro and in silico. We found that (1) star-shaped pGG analogs exhibit HA-inhibition activity by interacting with the conserved structural elements of the receptor binding domain (RBD); (2) HA inhibition depends on the number of galloyl substituents in a pGG analog; the best number is four; and when PGG binds with two HA trimers at their conserved receptor binding domains (loop 130, loop 220, and 190-α-helix), PGG acts as a molecular glue by aggregating viral particles so as to prevent viral entry into host cells (this was revealed via an in silico simulation on the binding of penta-galloyl-glucose (PGG) with HA). pGGs are also effective on a broad-spectrum influenza A subtypes (including H1, H3, H5, H7); this suggests that pGG analogs can be applied to most influenza A subtypes as a prophylactic against influenza viral infections.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Chickens
Conserved Sequence
Cross-Linking Reagents / pharmacology
Glucose / analogs & derivatives
Glucose / pharmacology*
Hemagglutination / drug effects
Hemagglutinin Glycoproteins, Influenza Virus / chemistry
Hemagglutinin Glycoproteins, Influenza Virus / metabolism
Host-Pathogen Interactions / drug effects
Hydrogen Bonding
Influenza A virus / drug effects
Influenza A virus / pathogenicity
Influenza A virus / physiology*
Influenza A virus / ultrastructure
Molecular Sequence Data
N-Acetylneuraminic Acid / pharmacology
Protein Structure, Tertiary
Receptors, Virus / metabolism
Thermodynamics
Virion / drug effects
Virion / metabolism
Virion / ultrastructure
Virus Internalization / drug effects*

Substances

Cross-Linking Reagents
Hemagglutinin Glycoproteins, Influenza Virus
Receptors, Virus
N-Acetylneuraminic Acid
Glucose

Grants and funding

This work was supported by a grant from the National High Technology Research and Development Program of China (863 Program) (No. 2012AA020307), Guangdong Recruitment Program of Creative Research Groups, and the National Natural Science Foundation of China (No. 81173470, 81274170), and the Special Funding Program for the National Supercomputer Center in Guangzhou (2012Y2-00048/2013Y2-00045, 201200000037). This study was also supported partly by Grant-in-aid from the Tokyo Biochemical Research Foundation and a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (No. 22590274). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.