Inhibition of Biosynthesis and Biochemical Modulation of N-Acylneuraminic Acid (Biochemical Engineering of Sialoconjugates). A Review

The key enzyme of sialic acid biosynthesis is the bifunctional UDP-GlcNAc 2-epimerase/ ManNAc kinase. Novel inhibitors of this enzyme have been synthesized. TheN-acyl side chain of sialic acid can be biochemically engineered by incubating cells with non-naturalN-acylmannosamine analogues such asN-propionylmannosamine and related compounds. These modified sialic acids lead to various biological changes, such as stimulation of T-lymphocyte proliferation, inhibition of the uptake of influenza A virus, stimulation of neuritic growth, increased expression of sialyl-Lewisxand altered adhesion. A review with 41 references.

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Biochemical engineering of theN-acyl side chain of sialic acid leads to increased calcium influx from intracellular compartments and promotes differentiation of HL60 cells

FEBS Letters ◽

10.1016/j.febslet.2004.06.067 ◽

2004 ◽

Vol 571 (1-3) ◽

pp. 99-102 ◽

Cited By ~ 12

Author(s):

Rüdiger Horstkorte ◽

Kirstin Rau ◽

Stephan Laabs ◽

Kerstin Danker ◽

Werner Reutter

Keyword(s):

Sialic Acid ◽

Calcium Influx ◽

Side Chain ◽

Biochemical Engineering ◽

Hl60 Cells ◽

Acyl Side Chain ◽

Intracellular Compartments

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Biochemical engineering of the N-acyl side chain of sialic acid: biological implications

Glycobiology ◽

10.1093/glycob/11.2.11r ◽

2001 ◽

Vol 11 (2) ◽

pp. 11R-18R ◽

Cited By ~ 210

Author(s):

O. T. Keppler ◽

R. Horstkorte ◽

M. Pawlita ◽

C. Schmidt ◽

W. Reutter

Keyword(s):

Sialic Acid ◽

Side Chain ◽

Biochemical Engineering ◽

Acyl Side Chain

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Potent sialic acid inhibitors that target influenza A virus hemagglutinin

Scientific Reports ◽

10.1038/s41598-021-87845-0 ◽

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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Compartmentalization of corticotropin-dependent steroidogenic factors in adrenal cortex: evidence for a post-translational cascade in stimulation of the cholesterol side-chain split.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.79.6.1727 ◽

1982 ◽

Vol 79 (6) ◽

pp. 1727-1731 ◽

Cited By ~ 17

Author(s):

R. Neher ◽

A. Milani ◽

A. R. Solano ◽

E. J. Podesta

Keyword(s):

Adrenal Cortex ◽

Side Chain ◽

Stimulation Of

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N-Glycolylneuraminic Acid in Animal Models for Human Influenza A Virus

Viruses ◽

10.3390/v13050815 ◽

2021 ◽

Vol 13 (5) ◽

pp. 815

Author(s):

Cindy M. Spruit ◽

Nikoloz Nemanichvili ◽

Masatoshi Okamatsu ◽

Hiromu Takematsu ◽

Geert-Jan Boons ◽

...

Keyword(s):

Sialic Acid ◽

Animal Models ◽

Influenza A ◽

Influenza Virus Infection ◽

Influenza Viruses ◽

Upper Respiratory Tract ◽

Human Influenza ◽

Influenza A Viruses ◽

Sialic Acid Content ◽

Acetylneuraminic Acid

The first step in influenza virus infection is the binding of hemagglutinin to sialic acid-containing glycans present on the cell surface. Over 50 different sialic acid modifications are known, of which N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc) are the two main species. Animal models with α2,6 linked Neu5Ac in the upper respiratory tract, similar to humans, are preferred to enable and mimic infection with unadapted human influenza A viruses. Animal models that are currently most often used to study human influenza are mice and ferrets. Additionally, guinea pigs, cotton rats, Syrian hamsters, tree shrews, domestic swine, and non-human primates (macaques and marmosets) are discussed. The presence of NeuGc and the distribution of sialic acid linkages in the most commonly used models is summarized and experimentally determined. We also evaluated the role of Neu5Gc in infection using Neu5Gc binding viruses and cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH)-/- knockout mice, which lack Neu5Gc and concluded that Neu5Gc is unlikely to be a decoy receptor. This article provides a base for choosing an appropriate animal model. Although mice are one of the most favored models, they are hardly naturally susceptible to infection with human influenza viruses, possibly because they express mainly α2,3 linked sialic acids with both Neu5Ac and Neu5Gc modifications. We suggest using ferrets, which resemble humans closely in the sialic acid content, both in the linkages and the lack of Neu5Gc, lung organization, susceptibility, and disease pathogenesis.

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Modulation of Antigen Display on PapMV Nanoparticles Influences Its Immunogenicity

Vaccines ◽

10.3390/vaccines9010033 ◽

2021 ◽

Vol 9 (1) ◽

pp. 33

Author(s):

Marie-Eve Laliberté-Gagné ◽

Marilène Bolduc ◽

Caroline Garneau ◽

Santa-Mariela Olivera-Ugarte ◽

Pierre Savard ◽

...

Keyword(s):

Immune Response ◽

Influenza A ◽

Matrix Protein ◽

Cell Epitope ◽

Vaccine Antigen ◽

Vaccine Platform ◽

Peptide Antigens ◽

C Terminus ◽

The Impact ◽

Stimulation Of

Background: The papaya mosaic virus (PapMV) vaccine platform is a rod-shaped nanoparticle made of the recombinant PapMV coat protein (CP) self-assembled around a noncoding single-stranded RNA (ssRNA) template. The PapMV nanoparticle induces innate immunity through stimulation of the Toll-like receptors (TLR) 7 and 8. The display of the vaccine antigen at the surface of the nanoparticle, associated with the co-stimulation signal via TLR7/8, ensures a strong stimulation of the immune response, which is ideal for the development of candidate vaccines. In this study, we assess the impact of where the peptide antigen is fused, whether at the surface or at the extremities of the nanoparticles, on the immune response directed to that antigen. Methods: Two different peptides from influenza A virus were used as model antigens. The conserved M2e peptide, derived from the matrix protein 2 was chosen as the B-cell epitope, and a peptide derived from the nucleocapsid was chosen as the cytotoxic T lymphocytes (CTL) epitope. These peptides were coupled at two different positions on the PapMV CP, the N- (PapMV-N) or the C-terminus (PapMV-C), using the transpeptidase activity of Sortase A (SrtA). The immune responses, both humoral and CD8+ T-cell-mediated, directed to the peptide antigens in the two different fusion contexts were analyzed and compared. The impact of coupling density at the surface of the nanoparticle was also investigated. Conclusions: The results demonstrate that coupling of the peptide antigens at the N-terminus (PapMV-N) of the PapMV CP led to an enhanced immune response to the coupled peptide antigens as compared to coupling to the C-terminus. The difference between the two vaccine platforms is linked to the enhanced capacity of the PapMV-N vaccine platform to stimulate TLR7/8. We also demonstrated that the strength of the immune response increases with the density of coupling at the surface of the nanoparticles.

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Protein-bound sialic acid in saliva contributes directly to salivary anti-influenza virus activity

10.1101/2021.03.05.433813 ◽

2021 ◽

Author(s):

Kaori Kobayashi ◽

Chika Shono ◽

Takuya Mori ◽

Hidefumi Kitazawa ◽

Noriyasu Ota ◽

...

Keyword(s):

Sialic Acid ◽

Influenza A ◽

Significant Positive Correlation ◽

Influenza Infection ◽

Respiratory Viruses ◽

Biological Factor ◽

Virus Activity ◽

Individual Variations ◽

Antiviral Activities ◽

Direct Regulator

ABSTRACTThe oral cavity is an entrance for respiratory viruses, such as influenza. Recently, saliva has been shown to exert both antimicrobial and antiviral activities. Thus, saliva may be a biological factor that contributes to the prevention of influenza infection. However, the actual salivary anti-influenza A virus (IAV) activity in individuals and its determinant factors are unknown. By assessing individual variations in salivary anti-IAV activity in 92 people using an established new high-throughput system in this study, we found that the anti-IAV activity varied widely between individuals and showed a significant positive correlation with protein-bound sialic acid (BSA) level (ρ=0.473; p < 0.001). Furthermore, the anti-IAV activity of saliva with enzymatically reduced BSA content was significantly lower. These results indicate that BSA is a direct regulator of salivary anti-IAV activity and is a determinant of individual differences. Additionally, after comparing the anti-IAV activity across the groups by age, anti-IAV activity in young people (aged 5–19 years) were lower than in adults aged 20–59 years and elderly people aged 60–79 years. Our study suggests that BSA levels in saliva may be important in preventing influenza infection.

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