Influenza A Virus Entry Inhibitors Targeting the Hemagglutinin

Yang, Jie; Li, Minmin; Shen, Xintian; Liu, Shuwen

doi:10.3390/v5010352

Cited by 102 publications

(73 citation statements)

References 88 publications

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“…The most abundant influenza virus transmembrane protein, hemagglutinin (HA), plays a key role at this stage. There are currently 18 known HA subtypes, which can be divided into 5 clades and 2 groups, group 1 HAs and group 2 HAs (11,12). HA consists of two polypeptide chains, HA 1 and HA 2 , linked by a disulfide bond, and exists as a trimeric glycoprotein on the viral envelope (12).…”

Section: Here We Report Two Structurally Distinctive Novel Fusion Inhmentioning

confidence: 99%

“…There are currently 18 known HA subtypes, which can be divided into 5 clades and 2 groups, group 1 HAs and group 2 HAs (11,12). HA consists of two polypeptide chains, HA 1 and HA 2 , linked by a disulfide bond, and exists as a trimeric glycoprotein on the viral envelope (12). The receptor binding subdomain of HA 1 recognizes and binds to ␣-2,3-or ␣-2,6-linked terminal sialic acids on the host cell on the basis of the receptor binding specificity of HA (12).…”

Section: Here We Report Two Structurally Distinctive Novel Fusion Inhmentioning

confidence: 99%

“…HA consists of two polypeptide chains, HA 1 and HA 2 , linked by a disulfide bond, and exists as a trimeric glycoprotein on the viral envelope (12). The receptor binding subdomain of HA 1 recognizes and binds to ␣-2,3-or ␣-2,6-linked terminal sialic acids on the host cell on the basis of the receptor binding specificity of HA (12). After attachment, the virion is internalized by receptor-mediated endocytosis.…”

Section: Here We Report Two Structurally Distinctive Novel Fusion Inhmentioning

confidence: 99%

“…This peptide is inserted into the endosomal membrane, resulting in the fusion of the viral and endosomal membranes. This allows the release of viral content into the cytoplasm of the cell, signifying the success of the entry during virus infection (12)(13)(14).…”

Section: Here We Report Two Structurally Distinctive Novel Fusion Inhmentioning

confidence: 99%

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Identification of Novel Fusion Inhibitors of Influenza A Virus by Chemical Genetics

Lai

Cheung

Yang

et al. 2016

J Virol

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A previous screening of more than 50,000 compounds led to the identification of a pool of bioactive small molecules with inhibitory effect on the influenza A virus. One of these compounds, now widely known as nucleozin, is a small molecule that targets the influenza A virus nucleoprotein. Here we identify and characterize two structurally different novel fusion inhibitors of the influenza A virus group 1 hemagglutinin (HA), FA-583 and FA-617, with low nanomolar activities. Escape mutants that are highly resistant to each of these compounds were generated, and both were found to carry mutations localized in close proximity to the B-loop of the hemagglutinin 2 protein, which plays a crucial role in the virion-host cell fusion process. Recombinant virus, generated through reverse genetics, confirmed the resistance phenotype. In addition, the proposed binding pockets predicted by molecular docking studies are in accordance with the resistance-bearing mutation sites. We show through mechanistic studies that FA-583 and FA-617 act as fusion inhibitors by prohibiting the low-pH-induced conformational change of hemagglutinin. Our study has offered concrete biological and mechanistic explorations for the strategic development of novel fusion inhibitors of influenza A viruses. IMPORTANCE Here we report two structurally distinctive novel fusion inhibitors of influenza

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Section: Here We Report Two Structurally Distinctive Novel Fusion Inhmentioning

confidence: 99%

Section: Here We Report Two Structurally Distinctive Novel Fusion Inhmentioning

confidence: 99%

Section: Here We Report Two Structurally Distinctive Novel Fusion Inhmentioning

confidence: 99%

Section: Here We Report Two Structurally Distinctive Novel Fusion Inhmentioning

confidence: 99%

See 2 more Smart Citations

Identification of Novel Fusion Inhibitors of Influenza A Virus by Chemical Genetics

Lai

Cheung

Yang

et al. 2016

J Virol

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“…Currently, there are two classes of antiviral drugs that are effective against influenza: M2 inhibitors, including amantadine and rimantadine, and the neuraminidase inhibitors Tamiflu and Relenza. 10 Most circulating influenza strains are resistant to the former class of drugs, and Tamiflu-resistant strains of H5N1 have recently emerged. Additionally, no vaccine has been developed yet that provides lasting protection against influenza infection.…”

Section: Introductionmentioning

confidence: 99%

Droplet microfluidics for kinetic studies of viral fusion

Mashaghi

Oijen

2016

Biomicrofluidics

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Viral infections remain a major threat to public health. The speed with which viruses are evolving drug-resistant mutations necessitates the further development of antiviral therapies with a large emphasis on drug discovery. To facilitate these efforts, there is a need for robust, high-throughput assays that allow the screening of large libraries of compounds, while enabling access to detailed kinetic data on their antiviral activity. We report here the development of a droplet-based microfluidic platform to probe viral fusion, an early critical step in infection by membrane-enveloped viruses such as HIV, Hepatitis C, and influenza. Using influenza A, we demonstrate the measurement of the kinetics of fusion of virions with target liposomes with sub-second temporal resolution. In analogy with acidification of the endosome that triggers fusion in a cellular context, we acidify the content of aqueous droplets containing virions and liposomes in situ by introducing acid from the dispersed phase and visualize the kinetics of fusion by using fluorescent probes.

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A new role of neuraminidase (NA) in the influenza virus life cycle: implication for developing NA inhibitors with novel mechanism of action

Yang

Liu

et al. 2016

Rev. Med. Virol.

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The entire life cycle of influenza virus involves viral attachment, entry, replication, and release. Previous studies have demonstrated that neuraminidase (NA) is an essential glycoprotein on the surface of influenza virus and that it is responsible for release of progeny virions from the host cell to infect new cells. However, recent studies have also suggested that NA may play other roles in the early stages of the viral life cycle, that is, viral attachment and entry. This review focuses on the new role of NA in the early stages of influenza life cycle and the corresponding development of novel NA inhibitors. Copyright © 2016 John Wiley & Sons, Ltd.

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Influenza A Virus Entry Inhibitors Targeting the Hemagglutinin

Cited by 102 publications

References 88 publications

Identification of Novel Fusion Inhibitors of Influenza A Virus by Chemical Genetics

Identification of Novel Fusion Inhibitors of Influenza A Virus by Chemical Genetics

Droplet microfluidics for kinetic studies of viral fusion

A new role of neuraminidase (NA) in the influenza virus life cycle: implication for developing NA inhibitors with novel mechanism of action

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