scholarly journals MD simulation of the interaction between sialoglycans and the second sialic acid binding site of influenza A virus N1 neuraminidase

2021 ◽  
Vol 478 (2) ◽  
pp. 423-441
Author(s):  
Stefano Elli ◽  
Nicola Gambacorta ◽  
Timothy R. Rudd ◽  
Mikhail Matrosovich ◽  
Marco Guerrini
Keyword(s):  
Sialic Acid ◽  
Binding Site ◽  
Influenza A ◽  
Md Simulation ◽  
Current Knowledge ◽  
Influenza Viruses ◽  
Molecular Features ◽  
Sialic Acid Binding ◽  
Glycan Receptors ◽  
Glycosidic Conformation

The neuraminidases (NAs) of avian influenza viruses (IAVs) contain a second sialic acid-binding site (2SBS), historically known as the hemadsorption site, which is separated from the sialyl-hydrolase catalytic site and serves to facilitate NA catalytic activity towards multivalent sialyl-capped glycoconjugates. Transmission and adaptation of avian IAVs to humans decreases hemadsorption and catalytic activities of the NA. Here, we report the molecular recognition features of the NA 2SBS of two pandemic H1N1 IAVs, A/Brevig Mission /1/1918 (BM18) and A/California/04/2009 (CA09), differing by their 2SBS activity. Using explicit solvent MD simulation, molecular mechanics, and glycosidic conformation analysis we initially analyzed the interactions of BM18 2SBS with two sialyllacto-N-tetraose pentasaccharides, 3′SLN-LC and 6′SLN-LC, which are models for the glycan receptors of IAVs in birds and humans, respectively. These studies characterize the binding specificity of BM18 2SBS towards human-type and avian-type receptors and identifies the key amino acids that affects binding. We next compared the interactions of the 2SBSs of BM18 and CA09 with 6′SLN-LC, revealing the critical effect of amino acid 372 on binding. Our results expand the current knowledge of the molecular features of NA 2SBSs and its alteration during the adaptation of avian IAVs to humans.

scholarly journals Role of Sialic Acid Binding Specificity of the 1918 Influenza Virus Hemagglutinin Protein in Virulence and Pathogenesis for Mice

2009 ◽  
Vol 83 (8) ◽  
pp. 3754-3761 ◽  
Author(s):  
Li Qi ◽  
John C. Kash ◽  
Vivien G. Dugan ◽  
Ruixue Wang ◽  
Guozhong Jin ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Sialic Acid ◽  
Influenza A ◽  
Influenza Pandemic ◽  
Binding Specificity ◽  
Influenza Viruses ◽  
Virulence Determinants ◽  
Sialic Acid Binding ◽  
1918 Influenza

ABSTRACT The 1918 influenza pandemic caused more than 40 million deaths and likely resulted from the introduction and adaptation of a novel avian-like virus. Influenza A virus hemagglutinins are important in host switching and virulence. Avian-adapted influenza virus hemagglutinins bind sialic acid receptors linked via α2-3 glycosidic bonds, while human-adapted hemagglutinins bind α2-6 receptors. Sequence analysis of 1918 isolates showed hemagglutinin genes with α2-6 or mixed α2-6/α2-3 binding. To characterize the role of the sialic acid binding specificity of the 1918 hemagglutinin, we evaluated in mice chimeric influenza viruses expressing wild-type and mutant hemagglutinin genes from avian and 1918 strains with differing receptor specificities. Viruses expressing 1918 hemagglutinin possessing either α2-6, α2-3, or α2-3/α2-6 sialic acid specificity were fatal to mice, with similar pathology and cellular tropism. Changing α2-3 to α2-6 binding specificity did not increase the lethality of an avian-adapted hemagglutinin. Thus, the 1918 hemagglutinin contains murine virulence determinants independent of receptor binding specificity.

scholarly journals The 2nd sialic acid-binding site of influenza A virus neuraminidase is an important determinant of the hemagglutinin-neuraminidase-receptor balance

2019 ◽  
Vol 15 (6) ◽  
pp. e1007860 ◽  
Author(s):  
Wenjuan Du ◽  
Hongbo Guo ◽  
Vera S. Nijman ◽  
Jennifer Doedt ◽  
Erhard van der Vries ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Binding Site ◽  
Influenza A Virus ◽  
Influenza A ◽  
Important Determinant ◽  
Sialic Acid Binding

scholarly journals Influenza binds phosphorylated glycans from human lung

2019 ◽  
Vol 5 (2) ◽  
pp. eaav2554 ◽  
Author(s):  
Lauren Byrd-Leotis ◽  
Nan Jia ◽  
Sucharita Dutta ◽  
Jessica F. Trost ◽  
Chao Gao ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Influenza A ◽  
Human Lung ◽  
Species Specificity ◽  
Influenza Viruses ◽  
Surface Markers ◽  
Influenza A Viruses ◽  
Synthetic Receptor ◽  
Glycan Receptors ◽  
Sialic Acid Linkage

Influenza A viruses can bind sialic acid–terminating glycan receptors, and species specificity is often correlated with sialic acid linkage with avian strains recognizing α2,3-linked sialylated glycans and mammalian strains preferring α2,6-linked sialylated glycans. These paradigms derive primarily from studies involving erythrocyte agglutination, binding to synthetic receptor analogs or binding to undefined surface markers on cells or tissues. Here, we present the first examination of the N-glycome of the human lung for identifying natural receptors for a range of avian and mammalian influenza viruses. We found that the human lung contains many α2,3- and α2,6-linked sialylated glycan determinants bound by virus, but all viruses also bound to phosphorylated, nonsialylated glycans.

scholarly journals Breaking the Convention: Sialoglycan Variants, Coreceptors, and Alternative Receptors for Influenza A Virus Entry

2019 ◽  
Vol 94 (4) ◽  
Author(s):  
Umut Karakus ◽  
Marie O. Pohl ◽  
Silke Stertz
Keyword(s):  
Sialic Acid ◽  
Influenza A Virus ◽  
Mhc Class Ii ◽  
Influenza A ◽  
Current Knowledge ◽  
Cell Receptor ◽  
Host Cell Receptor ◽  
Histocompatibility Complex ◽  
Sialic Acid Binding ◽  
Review Current

ABSTRACT The influenza A virus (IAV) envelope protein hemagglutinin binds α2,6- or α2,3-linked sialic acid as a host cell receptor. Bat IAV subtypes H17N10 and H18N11 form an exception to this rule and do not bind sialic acid but enter cells via major histocompatibility complex (MHC) class II. Here, we review current knowledge on IAV receptors with a focus on sialoglycan variants, protein coreceptors, and alternative receptors that impact IAV attachment and internalization beyond the well-described sialic acid binding.

scholarly journals Mutation of the Second Sialic Acid-Binding Site, Resulting in Reduced Neuraminidase Activity, Preceded the Emergence of H7N9 Influenza A Virus

2017 ◽  
Vol 91 (9) ◽  
Author(s):  
Meiling Dai ◽  
Ryan McBride ◽  
Jos C. F. M. Dortmans ◽  
Wenjie Peng ◽  
Mark J. G. Bakkers ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Binding Site ◽  
Influenza A Virus ◽  
Receptor Binding ◽  
Host Species ◽  
Influenza A ◽  
The Novel ◽  
Species Barrier ◽  
Binding Properties ◽  
Sialic Acid Binding

ABSTRACT The emergence of the novel influenza A virus (IAV) H7N9 since 2013 has caused concerns about the ability of the virus to spread between humans. Analysis of the receptor-binding properties of the H7 protein of a human isolate revealed modestly increased binding to α2,6 sialosides and reduced, but still dominant, binding to α2,3-linked sialic acids (SIAs) compared to a closely related avian H7N9 virus from 2008. Here, we show that the corresponding N9 neuraminidases (NAs) display equal enzymatic activities on a soluble monovalent substrate and similar substrate specificities on a glycan array. In contrast, solid-phase activity and binding assays demonstrated reduced specific activity and decreased binding of the novel N9 protein. Mutational analysis showed that these differences resulted from substitution T401A in the 2nd SIA-binding site, indicating that substrate binding via this site enhances NA catalytic activity. Substitution T401A in the novel N9 protein appears to functionally mimic the substitutions that are found in the 2nd SIA-binding site of NA proteins of avian-derived IAVs that became human pandemic viruses. Our phylogenetic analyses show that substitution T401A occurred prior to substitutions in hemagglutinin (HA), causing the altered receptor-binding properties mentioned above. Hence, in contrast to the widespread assumption that such changes in NA are obtained only after acquisition of functional changes in HA, our data indicate that mutations in the 2nd SIA-binding site may have enabled and even driven the acquisition of altered HA receptor-binding properties and may have contributed to the spread of the novel H7N9 viruses. IMPORTANCE Novel H7N9 IAVs continue to cause human infections and pose an ongoing public health threat. Here, we show that their N9 proteins display reduced binding to and lower enzymatic activity against multivalent substrates, resulting from mutation of the 2nd sialic acid-binding site. This mutation preceded and may have driven the selection of substitutions in H7 that modify H7 receptor-binding properties. Of note, all animal IAVs that managed to cross the host species barrier and became human viruses carry mutated 2nd sialic acid-binding sites. Screening of animal IAVs to monitor their potential to cross the host species barrier should therefore focus not only on the HA protein, but also on the functional properties of NA.

scholarly journals Mutation of the second sialic acid-binding site of influenza A virus neuraminidase drives compensatory mutations in hemagglutinin

2020 ◽  
Vol 16 (8) ◽  
pp. e1008816 ◽  
Author(s):  
Wenjuan Du ◽  
Margreet A. Wolfert ◽  
Ben Peeters ◽  
Frank J. M. van Kuppeveld ◽  
Geert-Jan Boons ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Binding Site ◽  
Influenza A Virus ◽  
Influenza A ◽  
Sialic Acid Binding ◽  
Compensatory Mutations

scholarly journals Second sialic acid‐binding site of influenza A virus neuraminidase: binding receptors for efficient release

FEBS Journal ◽  
2020 ◽  
Author(s):  
Wenjuan Du ◽  
Erik de Vries ◽  
Frank J. M. van Kuppeveld ◽  
Mikhail Matrosovich ◽  
Cornelis A. M. de Haan
Keyword(s):  
Sialic Acid ◽  
Binding Site ◽  
Influenza A Virus ◽  
Influenza A ◽  
Sialic Acid Binding

scholarly journals Potent sialic acid inhibitors that target influenza A virus hemagglutinin

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yu-Jen Chang ◽  
Cheng-Yun Yeh ◽  
Ju-Chien Cheng ◽  
Yu-Qi Huang ◽  
Kai-Cheng Hsu ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Antiviral Activity ◽  
Binding Site ◽  
Influenza A Virus ◽  
Receptor Binding ◽  
Influenza A ◽  
The United States ◽  
Ligand Complex ◽  
Receptor Binding Site ◽  
Computational Strategy

AbstractEradicating influenza A virus (IAV) is difficult, due to its genetic drift and reassortment ability. As the infectious cycle is initiated by the influenza glycoprotein, hemagglutinin (HA), which mediates the binding of virions to terminal sialic acids moieties, HA is a tempting target of anti-influenza inhibitors. However, the complexity of the HA structure has prevented delineation of the structural characterization of the HA protein–ligand complex. Our computational strategy efficiently analyzed > 200,000 records of compounds held in the United States National Cancer Institute (NCI) database and identified potential HA inhibitors, by modeling the sialic acid (SA) receptor binding site (RBS) for the HA structure. Our modeling revealed that compound NSC85561 showed significant antiviral activity against the IAV H1N1 strain with EC50 values ranging from 2.31 to 2.53 µM and negligible cytotoxicity (CC50 > 700 µM). Using the NSC85561 compound as the template to generate 12 derivatives, robust bioassay results revealed the strongest antiviral efficacies with NSC47715 and NSC7223. Virtual screening clearly identified three SA receptor binding site inhibitors that were successfully validated in experimental data. Thus, our computational strategy has identified SA receptor binding site inhibitors against HA that show IAV-associated antiviral activity.

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