scholarly journals Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase

2010 ◽  
Vol 1 (1) ◽  
Author(s):  
Santosh Rudrawar ◽  
Jeffrey C. Dyason ◽  
Marie-Anne Rameix-Welti ◽  
Faith J. Rose ◽  
Philip S. Kerry ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Influenza A Virus ◽  
Influenza A ◽  
Virus Group ◽  
Group 1

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.

Quantification of Multivalent Interactions between Sialic Acid and Influenza A Virus Spike Proteins by Single-Molecule Force Spectroscopy

2020 ◽  
Vol 142 (28) ◽  
pp. 12181-12192 ◽  
Author(s):  
Jose Luis Cuellar-Camacho ◽  
Sumati Bhatia ◽  
Valentin Reiter-Scherer ◽  
Daniel Lauster ◽  
Susanne Liese ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Influenza A Virus ◽  
Single Molecule ◽  
Influenza A ◽  
Force Spectroscopy ◽  
Single Molecule Force Spectroscopy ◽  
Multivalent Interactions ◽  
Spike Proteins

scholarly journals Infection of Human Airway Epithelium by Human and Avian Strains of Influenza A Virus

2006 ◽  
Vol 80 (16) ◽  
pp. 8060-8068 ◽  
Author(s):  
Catherine I. Thompson ◽  
Wendy S. Barclay ◽  
Maria C. Zambon ◽  
Raymond J. Pickles
Keyword(s):  
Sialic Acid ◽  
Avian Influenza ◽  
Influenza A Virus ◽  
Airway Epithelium ◽  
Influenza A ◽  
Cell Types ◽  
Influenza Viruses ◽  
Apical Surface ◽  
Ciliated Cells ◽  
Human Viruses

ABSTRACT We describe the characterization of influenza A virus infection of an established in vitro model of human pseudostratified mucociliary airway epithelium (HAE). Sialic acid receptors for both human and avian viruses, α-2,6- and α-2,3-linked sialic acids, respectively, were detected on the HAE cell surface, and their distribution accurately reflected that in human tracheobronchial tissue. Nonciliated cells present a higher proportion of α-2,6-linked sialic acid, while ciliated cells possess both sialic acid linkages. Although we found that human influenza viruses infected both ciliated and nonciliated cell types in the first round of infection, recent human H3N2 viruses infected a higher proportion of nonciliated cells in HAE than a 1968 pandemic-era human virus, which infected proportionally more ciliated cells. In contrast, avian influenza viruses exclusively infected ciliated cells. Although a broad-range neuraminidase abolished infection of HAE by human parainfluenza virus type 3, this treatment did not significantly affect infection by influenza viruses. All human viruses replicated efficiently in HAE, leading to accumulation of nascent virus released from the apical surface between 6 and 24 h postinfection with a low multiplicity of infection. Avian influenza A viruses also infected HAE, but spread was limited compared to that of human viruses. The nonciliated cell tropism of recent human H3N2 viruses reflects a preference for the sialic acid linkages displayed on these cell types and suggests a drift in the receptor binding phenotype of the H3 hemagglutinin protein as it evolves in humans away from its avian virus precursor.

scholarly journals Influenza A virus surface proteins are organized to help penetrate host mucus

2019 ◽  
Author(s):  
Michael D. Vahey ◽  
Daniel A. Fletcher
Keyword(s):  
Sialic Acid ◽  
Influenza A Virus ◽  
Influenza A ◽  
Spatial Organization ◽  
Super Resolution ◽  
Fluorescent Labeling ◽  
Viral Envelope ◽  
Surface Proteins ◽  
Virus Surface ◽  
Super Resolution Microscopy

AbstractInfluenza A virus (IAV) enters cells by binding to sialic acid on the cell surface. To accomplish this while avoiding immobilization by sialic acid in host mucus, viruses rely on a balance between the receptor-binding protein hemagglutinin (HA) and the receptor-cleaving protein neuraminidase (NA). Although genetic aspects of this balance are well-characterized, little is known about how the spatial organization of these proteins in the viral envelope may contribute. Using site-specific fluorescent labeling and super-resolution microscopy, we show that HA and NA are asymmetrically distributed on the surface of filamentous viruses, creating an organization of binding and cleaving activities that causes viruses to step consistently away from their NA-rich pole. This Brownian ratchet-like diffusion produces persistent directional mobility that resolves the virus’s conflicting needs to both penetrate mucus and stably attach to the underlying cells, and could contribute to the prevalence of the filamentous phenotype in clinical isolates of IAV.

scholarly journals Substrate Specificity of Equine and Human Influenza A Virus Sialidase to Molecular Species of Sialic Acid

2016 ◽  
Vol 39 (10) ◽  
pp. 1728-1733 ◽  
Author(s):  
Tadanobu Takahashi ◽  
Saori Unuma ◽  
Sawako Kawagishi ◽  
Yuuki Kurebayashi ◽  
Maiko Takano ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Substrate Specificity ◽  
Influenza A Virus ◽  
Molecular Species ◽  
Influenza A ◽  
Human Influenza

scholarly journals Influenza Viruses in Mice: Deep Sequencing Analysis of Serial Passage and Effects of Sialic Acid Structural Variation

2019 ◽  
Vol 93 (23) ◽  
Author(s):  
Brian R. Wasik ◽  
Ian E. H. Voorhees ◽  
Karen N. Barnard ◽  
Brynn K. Alford-Lawrence ◽  
Wendy S. Weichert ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Sialic Acid ◽  
Influenza A Virus ◽  
Deep Sequencing ◽  
Influenza A ◽  
Natural Host ◽  
H1n1 Pandemic ◽  
Influenza A Viruses ◽  
Canine Influenza Virus ◽  
Canine Influenza

ABSTRACT Influenza A viruses have regularly jumped to new host species to cause epidemics or pandemics, an evolutionary process that involves variation in the viral traits necessary to overcome host barriers and facilitate transmission. Mice are not a natural host for influenza virus but are frequently used as models in studies of pathogenesis, often after multiple passages to achieve higher viral titers that result in clinical disease such as weight loss or death. Here, we examine the processes of influenza A virus infection and evolution in mice by comparing single nucleotide variations of a human H1N1 pandemic virus, a seasonal H3N2 virus, and an H3N2 canine influenza virus during experimental passage. We also compared replication and sequence variation in wild-type mice expressing N-glycolylneuraminic acid (Neu5Gc) with those seen in mice expressing only N-acetylneuraminic acid (Neu5Ac). Viruses derived from plasmids were propagated in MDCK cells and then passaged in mice up to four times. Full-genome deep sequencing of the plasmids, cultured viruses, and viruses from mice at various passages revealed only small numbers of mutational changes. The H3N2 canine influenza virus showed increases in frequency of sporadic mutations in the PB2, PA, and NA segments. The H1N1 pandemic virus grew well in mice, and while it exhibited the maintenance of some minority mutations, there was no clear evidence for adaptive evolution. The H3N2 seasonal virus did not establish in the mice. Finally, there were no clear sequence differences associated with the presence or absence of Neu5Gc. IMPORTANCE Mice are commonly used as a model to study the growth and virulence of influenza A viruses in mammals but are not a natural host and have distinct sialic acid receptor profiles compared to humans. Using experimental infections with different subtypes of influenza A virus derived from different hosts, we found that evolution of influenza A virus in mice did not necessarily proceed through the linear accumulation of host-adaptive mutations, that there was variation in the patterns of mutations detected in each repetition, and that the mutation dynamics depended on the virus examined. In addition, variation in the viral receptor, sialic acid, did not affect influenza virus evolution in this model. Overall, our results show that while mice provide a useful animal model for influenza virus pathology, host passage evolution will vary depending on the specific virus tested.

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