Anti-influenza Activity of Povidone-Iodine-Integrated Materials.

Personal protective equipment (PPE), including medical masks, should be worn for preventing the transmission of respiratory pathogens via infective droplets and aerosols. In medical masks, the key layer is the filter layer, and the melt-blown nonwoven fabric (NWF) is the most used fabric. However, the NWF filter layer cannot kill or inactivate the pathogens spread via droplets and aerosols.

Influenza A Virus Neuraminidase Inhibitors.

Depending on the strain, influenza A virus causes animal, zoonotic, pandemic, or seasonal influenza with varying degrees of severity. Two surface glycoprotein spikes, hemagglutinin (HA) and neuraminidase (NA), are the most important influenza A virus antigens. NA plays an important role in the propagation of influenza virus by removing terminal sialic acid from sialyl decoy receptors and thereby facilitating the release of viruses from traps such as in mucus and on infected cells.

Synthesis and Neuraminidase Inhibitory Activity of Sialic Acid Analogues with Fluoro, Phosphono, and Sulfo Functionalities.

Methods to synthesize influenza virus inhibitors with fluoro, phosphono, and/or sulfo functional groups are described. The resulting sialic acid analogues are produced from the natural substrate N-acetylneuraminic acid as starting material. Fluorescent assay methods for inhibition of influenza neuraminidase and virus proliferation are also provided.

Roles of Sialyl Glycans in HCoV-OC43, HCoV-HKU1, MERS-CoV and SARS-CoV-2 Infections.

Ongoing seasonal HCoV-OC43 and HCoV-HKU1 (common cold), an ongoing zoonotic infection of highly lethal MERS-CoV in humans (MERS disease), and an ongoing pandemic SARS-CoV-2 (COVID-19) with high mutability giving some variants causing severe illness and death have been reported to attach to sialyl receptors via their spike (S) glycoproteins and via additional short spikes, hemagglutinin-esterase (HE) glycoproteins, for HCoV-OC43 and HCoV-HKU1. There is lack of zoonotic viruses that are origins of HCoV-HKU1 and the first recorded pandemic CoV (SARS-CoV-2) for studies. In this chapter, we review current knowledge of the roles of sialyl glycans in infections with these viruses in distinct infection stages.

Roles of Glycans and Non-glycans on the Epithelium and in the Immune System in H1-H18 Influenza A Virus Infections.

The large variation of influenza A viruses (IAVs) in various susceptible hosts and their rapid evolution, which allows host/tissue switching, host immune escape, vaccine escape, and drug resistance, are difficult challenges for influenza control in all countries worldwide. Access and binding of the IAV to actual receptors at endocytic sites is critical for the establishment of influenza infection. In this chapter, the progress in identification of and roles of glycans and non-glycans on the epithelium and in the immune system in H1-H18 IAV infections are reviewed.

Significant role of host sialylated glycans in the infection and spread of severe acute respiratory syndrome coronavirus 2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been transmitted across all over the world, in contrast to the limited epidemic of genetically- and virologically-related SARS-CoV. However, the molecular basis explaining the difference in the virological characteristics among SARS-CoV-2 and SARS-CoV has been poorly defined. Here we identified that host sialoglycans play a significant role in the efficient spread of SARS-CoV-2 infection, while this was not the case with SARS-CoV.

Host Receptors of Influenza Viruses and Coronaviruses-Molecular Mechanisms of Recognition.

Among the four genera of influenza viruses (IVs) and the four genera of coronaviruses (CoVs), zoonotic αIV and βCoV have occasionally caused airborne epidemic outbreaks in humans, who are immunologically naïve, and the outbreaks have resulted in high fatality rates as well as social and economic disruption and losses. The most devasting influenza A virus (IAV) in αIV, pandemic H1N1 in 1918, which caused at least 40 million deaths from about 500 million cases of infection, was the first recorded emergence of IAVs in humans. Usually, a novel human-adapted virus replaces the preexisting human-adapted virus.

Correction to: Hemagglutinin Inhibitors are Potential Future Anti-Influenza Drugs for Mono- and Combination Therapies.

The inadvertently published below contents have been corrected.

H9N2 Influenza Virus Infections in Human Cells Require a Balance between Neuraminidase Sialidase Activity and Hemagglutinin Receptor Affinity.

Some avian influenza (AI) viruses have a deletion of up to 20 to 30 amino acids in their neuraminidase (NA) stalk. This has been associated with changes in virus replication and host range. Currently prevalent H9N2 AI viruses have only a 2- or 3-amino-acid deletion, and such deletions were detected in G1 and Y280 lineage viruses, respectively.

Preparation and Detection of Glycan-Binding Activity of Influenza Virus.

We describe a method to detect influenza virus using an evanescent-field-activated fluorescence scanner type glycan array and ELISA system. Neoglycoprotein was prepared by combination of organic chemistry and biomaterial preparation. These ligands were spotted on a glass plate or plastic well to make a glycan array and ELISA plate.

Hemagglutinin Inhibitors are Potential Future Anti-Influenza Drugs for Mono- and Combination Therapies.

Infections by H1-H16 influenza A viruses require sufficient binding of viral hemagglutinins (HAs) to specific target receptors, glycoconjugates bearing sialyl sugar chains, on the host cell surface. Synthesized sialyl sugar chains targeting sialyl sugar-binding sites in HAs that are immutable as long as the virus does not switch to a different host species might therefore be highly effective candidate drugs for inhibition of the initial required step of virus entry. In this chapter, we describe the following aspects of updated sialyl sugar chains as influenza A virus HA inhibitors (HAIs): (1) mode of terminal sialyl-galactose linkage, (2) molecular length and structure of sialyl glycan receptors, (3) multivalent sialyl sugar chain dimension, (4) clustering of sialyl sugar chains on macromolecular scaffolds, and (5) enhancement of the stability of sialyl sugar chain HA inhibitors.

Sialoglycovirology of Lectins: Sialyl Glycan Binding of Enveloped and Non-enveloped Viruses.

On the cell sur "face", sialoglycoconjugates act as receptionists that have an important role in the first step of various cellular processes that bridge communication between the cell and its environment. Loss of Sia production can cause the developmental of defects and lethality in most animals; hence, animal cells are less prone to evolution of resistance to interactions by rapidly evolved Sia-binding viruses. Obligative intracellular viruses mostly have rapid evolution that allows escape from host immunity, leading to an epidemic variant, and that allows emergence of a novel strain, occasionally leading to pandemics that cause health-social-economic problems.

Design, Synthesis, and Biological Evaluation of EdAP, a 4'-Ethynyl-2'-Deoxyadenosine 5'-Monophosphate Analog, as a Potent Influenza a Inhibitor.

Influenza A viruses leading to infectious respiratory diseases cause seasonal epidemics and sometimes periodic global pandemics. Viral polymerase is an attractive target in inhibiting viral replication, and 4'-ethynyladenosine, which has been reported as a highly potent anti-human immunodeficiency virus (HIV) nucleoside derivative, can work as an anti-influenza agent. Herein, we designed and synthesized a 4'-ethynyl-2'-deoxyadenosine 5'-monophosphate analog called EdAP ().

Characterization of H5N1 Influenza Virus Quasispecies with Adaptive Hemagglutinin Mutations from Single-Virus Infections of Human Airway Cells.

Transmission of avian influenza (AI) viruses to mammals involves phylogenetic bottlenecks that select small numbers of variants for transmission to new host species. However, little is known about the AI virus quasispecies diversity that produces variants for virus adaptation to humans. Here, we analyzed the hemagglutinin (HA) genetic diversity produced during AI H5N1 single-virus infection of primary human airway cells and characterized the phenotypes of these variants.

N-glycan structures of human alveoli provide insight into influenza A virus infection and pathogenesis.

Unlabelled: The rapidly evolvable influenza A virus has caused pandemics linked to millions of deaths in the past century. Influenza A viruses are categorized by H (hemagglutinin; HA) and N (neuraminidase; NA) proteins expressed on the viral envelope surface. Analyses of past pandemics suggest that the HA gene segment comes from a nonhuman virus, which is then introduced into an immunologically naïve human population with potentially devastating consequences.

Synthesis and anti-influenza virus evaluation of triterpene-sialic acid conjugates.

We are interested in new non-natural glycosides with sialic acid conjugates and their biological activities. We report the synthesis of eleven non-natural occurring glycosides, which are triterpene (glycyrrhetinic acid and its derivatives)-sialic acid conjugates, and their inhibitory activities against influenza virus sialidases and influenza virus multiplication in MDCK host cells. Deoxoglycyrrhetol-sialic acid conjugates (6d and 6e) and oleanolic acid-sialic acid conjugates (7d and 7e) showed strong inhibitory activities against three subtypes of influenza virus sialidases.

A Novel Potent and Highly Specific Inhibitor against Influenza Viral N1-N9 Neuraminidases: Insight into Neuraminidase-Inhibitor Interactions.

People throughout the world continue to be at risk for death from influenza A virus, which is always creating a new variant. Here we present a new effective and specific anti-influenza viral neuraminidase (viNA) inhibitor, 9-cyclopropylcarbonylamino-4-guanidino-Neu5Ac2en (cPro-GUN). Like zanamivir, it is highly effective against N1-N9 avian and N1-N2 human viNAs, including H274Y oseltamivir-resistant N1 viNA, due to its C-6 portion still being anchored in the active site, different from the disruption of oseltamivir's C-6 anchoring by H274Y mutation.

Inhibition of PA endonuclease activity of influenza virus RNA polymerase by Kampo medicines.

To find a novel influenza inhibitor targeting the endonuclease activity of influenza A virus polymerase acidic protein (PA), which is essential for the acquisition of primers for viral mRNA transcription, seven Kampo extracts were tested in vitro for their ability to inhibit endonuclease activity of the recombinant PA protein that was expressed and purified from Escherichia coli. The Kampo medicines Kakkonto, Shosaikoto, Saikokeishito, Keishito, Maobushisaishinto, and Maoto, but not Chikujountanto, inhibited PA endonuclease activity in a dose-dependent manner. Our results indicate that Kampo medicines are good sources providing a structural lead for optimization of an influenza endonuclease inhibitor.

6SLN-lipo PGA specifically catches (coats) human influenza virus and synergizes neuraminidase-targeting drugs for human influenza therapeutic potential.

Objectives: The purpose of this study was to develop a new compound to overcome influenza epidemics and pandemics as well as drug resistance.

Methods: We synthesized a new compound carrying: (i) Neu5Acα2-6Galβ1-4GlcNAc (6SLN) for targeting immutable haemagglutinins (HAs) unless switched from human-type receptor preference; (ii) an acyl chain (lipo) for locking the compound with the viral HA via hydrophobic interactions; and (iii) a flexible poly-α-L-glutamic acid (PGA) for enhancing the compound solubility and for coating the viral surface, precluding accessibility of the PGA-coated virus to the negatively charged sialic acid on the host cell surface.

Results: 6SLN-lipo PGA appears to subvert binding of pandemic H1 and seasonal H3 HAs to receptors, as assessed by using guinea pig erythrocytes, which is critical for virus entry into host cells for multiplication.

A novel immunochromatographic system for easy-to-use detection of group 1 avian influenza viruses with acquired human-type receptor binding specificity.

A switch of viral hemagglutinin receptor binding specificity from bird-type α2,3- to human-type α2,6-linked sialic acid is necessary for an avian influenza virus to become a pandemic virus. In this study, an easy-to-use strip test to detect receptor binding specificity of influenza virus was developed. A biotinylated anti-hemagglutinin antibody that bound a broad range of group 1 influenza A viruses and latex-conjugated α2,3 (blue) and α2,6 (red) sialylglycopolymers were used in an immunochromatographic strip test, with avidin and lectin immobilized on a nitrocellulose membrane at test and control lines, respectively.

Molecular basis of a pandemic of avian-type influenza virus.

Despite heroic efforts to prevent the emergence of an influenza pandemic, avian influenza A virus has prevailed by crossing the species barriers to infect humans worldwide, occasionally with morbidity and mortality at unprecedented levels, and the virus later usually continues circulation in humans as a seasonal influenza virus, resulting in health-social-economic problems each year. Here, we review current knowledge of influenza viruses, their life cycle, interspecies transmission, and past pandemics and discuss the molecular basis of pandemic acquisition, notably of hemagglutinin (lectin) acting as a key contributor to change in host specificity in viral infection.

A simple viral neuraminidase-based detection for high-throughput screening of viral hemagglutinin-host receptor specificity.

The correlation between precise interactions of influenza A virus hemagglutinins with host cell surface glycans having terminal sialic acids and host range specificity has provoked the development of a high-throughput viral-receptor specificity assay. Here, we describe the use of the virus itself as a specific antibody coupled to enzymes (virus with neuraminidase spikes) for determining its binding specificity to glycans, a strategy that reduces not only the cost but also the tedious steps of adding primary and secondary antibodies and washing between each step. All of the steps, including coating the glycopolymers onto microtiter plates, virus binding, and visual and quantitative detection of fluorescence products that correlate well with the amount of glycan-bound viruses, can be done within 3 h.