The mechanism of poly-galloyl-glucoses preventing Influenza A virus entry into host cells.
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.
School of Pharmaceutical Sciences & Institute of Human Virology, Sun Yat-Sen University, Guangzhou, China.
Hu
H
Ge
Division of Molecular Pharmacology of Infectious agents, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
Ge
G
Liu
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.
Yang-Fei
YF
Xiang
School of Pharmaceutical Sciences & Institute of Human Virology, Sun Yat-Sen University, Guangzhou, China.
Yu
Y
Wang
Division of Molecular Pharmacology of Infectious agents, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
Chao-Wan
CW
Guo
School of Pharmaceutical Sciences & Institute of Human Virology, Sun Yat-Sen University, Guangzhou, China.
Nan-Hao
NH
Chen
Kunming Institute of Botany, the Chinese Academy of Sciences, Kunming, China.
Ying-Jun
YJ
Zhang
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.
Yi-Fei
YF
Wang
Division of Molecular Pharmacology of Infectious agents, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
Kaio
K
Kitazato
School of Pharmaceutical Sciences & Institute of Human Virology, Sun Yat-Sen University, Guangzhou, China.
Jun
J
Xu
D000595:Amino Acid Sequence; D000818:Animals; D002645:Chickens; D017124:Conserved Sequence; D003432:Cross-Linking Reagents / Q000494:pharmacology; D005947:Glucose / Q000031:analogs & derivatives / Q000494:pharmacology*; D006384:Hemagglutination / Q000187:drug effects; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006860:Hydrogen Bonding; D009980:Influenza A virus / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology* / Q000648:ultrastructure; D008969:Molecular Sequence Data; D019158:N-Acetylneuraminic Acid / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011991:Receptors, Virus / Q000378:metabolism; D013816:Thermodynamics; D014771:Virion / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D053586:Virus Internalization / Q000187:drug effects*
D003432:Cross-Linking Reagents; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011991:Receptors, Virus; D019158:N-Acetylneuraminic Acid; D005947:Glucose