Viral neuraminidase

Last updated
Neuraminidase
Neuraminidase Ribbon Diagram.jpg
Crystallographic structure of influenza neuraminidase in complex with the inhibitor 4-acetamido-3-hydroxy-5-nitro-benzoic acid. [1]
Identifiers
SymbolNeur
Pfam PF00064
Pfam clan CL0434
InterPro IPR001860
SCOP2 2bat / SCOPe / SUPFAM
CAZy GH34
CDD cd00260
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
PDB 1a14 , 1a4g , 1a4q , 1b9s , 1b9t , 1b9v , 1bji , 1f8b , 1f8c , 1f8d , 1f8e , 1inf , 1ing , 1inh , 1inv , 1inw , 1inx , 1iny , 1ivb , 1ivc , 1ivd , 1ive , 1ivf , 1ivg , 1l7f , 1l7g , 1l7h , 1mwe , 1nca , 1ncb , 1ncc , 1ncd , 1nma , 1nmb , 1nmc , 1nn2 , 1nna , 1nnb , 1nnc , 1nsb , 1nsc , 1nsd , 1v0z , 1vcj , 1w1x , 1w20 , 1w21 , 1xoe , 1xog , 2aep , 2aeq , 2b8h , 2bat , 2c4a , 2c4l , 2cml , 2ht5 , 2ht7 , 2ht8 , 2htq , 2htr , 2htu , 2htv , 2htw , 2hty , 2hu0 , 2hu4 , 2qwa , 2qwb , 2qwc , 2qwd , 2qwe , 2qwf , 2qwg , 2qwh , 2qwi , 2qwj , 2qwk , 3b7e , 3beq , 3ckz , 3cl0 , 3cl2 , 3cye , 3nn9 , 4nn9 , 5nn9 , 6nn9 , 7nn9
The structure of the influenza virus neuraminidase. PDB 2bat EBI.jpg
The structure of the influenza virus neuraminidase.
Structure of Influenza, showing neuraminidase marked as NA and hemagglutinin as HA Flu und legende color c.jpg
Structure of Influenza, showing neuraminidase marked as NA and hemagglutinin as HA
Influenza virus replication, showing how in step 6 the neuraminidase and hemagglutinin proteins incorporated into the host cell's membrane are used to escape. Virus Replication.svg
Influenza virus replication, showing how in step 6 the neuraminidase and hemagglutinin proteins incorporated into the host cell's membrane are used to escape.

Viral neuraminidase is a type of neuraminidase found on the surface of influenza viruses that enables the virus to be released from the host cell. Neuraminidases are enzymes that cleave sialic acid (also called neuraminic acid) groups from glycoproteins. Viral neuraminidase was discovered by Alfred Gottschalk at the Walter and Eliza Hall Institute in 1957. [3] Neuraminidase inhibitors are antiviral agents that inhibit influenza viral neuraminidase activity and are of major importance in the control of influenza. [4]

Contents

Viral neuraminidases are the members of the glycoside hydrolase family 34 CAZY GH_34 which comprises enzymes with only one known activity; sialidase or neuraminidase EC 3.2.1.18. Neuraminidases cleave the terminal sialic acid residues from carbohydrate chains in glycoproteins. Sialic acid is a negatively charged sugar associated with the protein and lipid portions of lipoproteins.[ citation needed ]

To infect a host cell, the influenza virus attaches to the exterior cell surface using hemagglutinin, a molecule found on the surface of the virus that binds to sialic acid groups. Sialic acids are found on various glycoproteins at the host cell surface. The virus then moves from sialic acid group to sialic acid group until it finds the proper cell surface receptor (whose identity remains unknown). [5] Neuraminadase enables this movement by cleaving sialic acid groups that hemagglutinin was attached to. After the virus has entered the cell and has replicated, new viral particles bud from the host cell membrane. The hemagglutinin on new viral particles remains attached to sialic acid groups of glycoproteins on the external cell surface and the surface of other viral particles; neuraminadase cleaves these groups and thereby allows the release of viral particles [6] and prevents self-aggregation. [5] Neuraminadase also facilitates the movement of virus particles in the presence of mucus rich in silicic acid. [5]

A single hemagglutinin-neuraminidase protein can combine neuraminidase and hemagglutinin functions, such as in mumps virus and human parainfluenza virus.[ citation needed ]

Function

The enzyme helps viruses to be released after budding from the plasma membrane of a host cell. Influenza virus membranes contain two glycoproteins: hemagglutinin and neuraminidase. While the hemagglutinin on the surface of the virion is needed for infection, its presence inhibits release of the particle after budding. Viral neuraminidase cleaves terminal sialic acid residues from glycan structures on the surface of the infected cell. This promotes the release of progeny viruses and the spread of the virus from the host cell to uninfected surrounding cells. Neuraminidase also cleaves sialic acid residues from viral proteins, preventing aggregation of viruses.[ medical citation needed ]

Inhibitors

Neuraminidase has been targeted in structure-based enzyme inhibitor design programmes that have resulted in the production of two drugs, zanamivir (Relenza) and oseltamivir (Tamiflu). Administration of neuraminidase inhibitors is a treatment that limits the severity and spread of viral infections. Neuraminidase inhibitors are useful for combating influenza infection: zanamivir, administered by inhalation; oseltamivir, administered orally; and under research is peramivir administered parenterally, that is through intravenous or intramuscular injection.[ citation needed ]

Neuraminidase inhibition resistance

On February 27, 2005, a 14-year-old Vietnamese girl was documented to be carrying an H5N1 influenza virus strain that was resistant to the drug oseltamivir. The drug is used to treat patients that have contracted influenza. However, the Vietnamese girl who had received a prophylactic dose (75 mg once a day) was found to be non-responsive to the medication. In growing fears of a global avian flu pandemic, scientists began to look for a cause of resistance to the Tamiflu medication. The cause was determined to be a histidine-to-tyrosine (amino acid) substitution at position 274 in its neuraminidase protein.[ citation needed ]

As strains of influenza are continuously mutating, it is essential that scientists quickly and efficiently determine the correct neuraminidase subtype that is responsible for the drug resistance in order to develop medications that will combat specific strains of influenza.[ citation needed ]

A new class of neuraminidase inhibitors that covalently attach to the enzyme have shown activity against drug-resistant virus in vitro. [7] [8]

Specificity

In ideal circumstances, influenza virus neuraminidase (NA) should act on the same type of receptor the virus hemagglutinin (HA) binds to, a phenomenon that does not always happen. It is not quite clear how the virus manages to function when there is no close match between the specificities of NA and HA.[ citation needed ]

Exo- and endo-

Neuraminidase enzymes can have endo- or exo-glycosidase activity, and are classified as EC 3.2.1.29 (endo-neuraminidase) [9] and EC 3.2.1.18 (exo-neuraminidases). [10] In general, mammalian sialic acid residues are at terminal positions (non-reducing end) in complex glycans, and so viral neuraminidases - which are exo-glycosidase enzymes - use these terminal residues as their substrates.[ citation needed ]

See also

Related Research Articles

<span class="mw-page-title-main">Antiviral drug</span> Medication used to treat a viral infection

Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Antiviral drugs are one class of antimicrobials, a larger group which also includes antibiotic, antifungal and antiparasitic drugs, or antiviral drugs based on monoclonal antibodies. Most antivirals are considered relatively harmless to the host, and therefore can be used to treat infections. They should be distinguished from virucides, which are not medication but deactivate or destroy virus particles, either inside or outside the body. Natural virucides are produced by some plants such as eucalyptus and Australian tea trees.

<i>Influenza A virus</i> Species of virus

Influenza A virus (IAV) is a pathogen that causes the flu in birds and some mammals, including humans. It is an RNA virus whose subtypes have been isolated from wild birds. Occasionally, it is transmitted from wild to domestic birds, and this may cause severe disease, outbreaks, or human influenza pandemics.

<span class="mw-page-title-main">Hemagglutinin (influenza)</span> Hemagglutinin of influenza virus

Influenza hemagglutinin (HA) or haemagglutinin[p] is a homotrimeric glycoprotein found on the surface of influenza viruses and is integral to its infectivity.

<span class="mw-page-title-main">Sialic acid</span> Class of chemical compounds

Sialic acids are a class of alpha-keto acid sugars with a nine-carbon backbone. The term "sialic acid" was first introduced by Swedish biochemist Gunnar Blix in 1952. The most common member of this group is N-acetylneuraminic acid found in animals and some prokaryotes.

<i>Orthomyxoviridae</i> Family of RNA viruses including the influenza viruses

Orthomyxoviridae is a family of negative-sense RNA viruses. It includes seven genera: Alphainfluenzavirus, Betainfluenzavirus, Gammainfluenzavirus, Deltainfluenzavirus, Isavirus, Thogotovirus, and Quaranjavirus. The first four genera contain viruses that cause influenza in birds and mammals, including humans. Isaviruses infect salmon; the thogotoviruses are arboviruses, infecting vertebrates and invertebrates. The Quaranjaviruses are also arboviruses, infecting vertebrates (birds) and invertebrates (arthropods).

<span class="mw-page-title-main">Zanamivir</span> Influenza medication

Zanamivir is a medication used to treat and prevent influenza caused by influenza A and influenza B viruses. It is a neuraminidase inhibitor and was developed by the Australian biotech firm Biota Holdings. It was licensed to Glaxo in 1990 and approved in the US in 1999, only for use as a treatment for influenza. In 2006, it was approved for prevention of influenza A and B. Zanamivir was the first neuraminidase inhibitor commercially developed. It is marketed by GlaxoSmithKline under the trade name Relenza as a powder for oral inhalation.

<span class="mw-page-title-main">Oseltamivir</span> Antiviral medication used against influenza A and influenza B

Oseltamivir, sold under the brand name Tamiflu, is an antiviral medication used to treat and prevent influenza A and influenza B, viruses that cause the flu. Many medical organizations recommend it in people who have complications or are at high risk of complications within 48 hours of first symptoms of infection. They recommend it to prevent infection in those at high risk, but not the general population. The Centers for Disease Control and Prevention (CDC) recommends that clinicians use their discretion to treat those at lower risk who present within 48 hours of first symptoms of infection. It is taken by mouth, either as a pill or liquid.

<span class="mw-page-title-main">Neuraminidase</span> Glycoside hydrolase enzymes that cleave the glycosidic linkages of neuraminic acids

Exo-α-sialidase is a glycoside hydrolase that cleaves the glycosidic linkages of neuraminic acids:

<span class="mw-page-title-main">Hemagglutinin esterase</span> Glycoprotein present in some enveloped viruses

Hemagglutinin esterase (HEs) is a glycoprotein that certain enveloped viruses possess and use as an invading mechanism. HEs helps in the attachment and destruction of certain sialic acid receptors that are found on the host cell surface. Viruses that possess HEs include influenza C virus, toroviruses, and coronaviruses of the subgenus Embecovirus. HEs is a dimer transmembrane protein consisting of two monomers, each monomer is made of three domains. The three domains are: membrane fusion, esterase, and receptor binding domains.

Neuraminidase inhibitors (NAIs) are a class of drugs which block the neuraminidase enzyme. They are a commonly used antiviral drug type against influenza. Viral neuraminidases are essential for influenza reproduction, facilitating viral budding from the host cell. Oseltamivir (Tamiflu), zanamivir (Relenza), laninamivir (Inavir), and peramivir belong to this class. Unlike the M2 inhibitors, which work only against the influenza A virus, NAIs act against both influenza A and influenza B.

<span class="mw-page-title-main">Peramivir</span> Antiviral drug targeting influenza

Peramivir is an antiviral drug developed by BioCryst Pharmaceuticals for the treatment of influenza. Peramivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells. It is approved for intravenous administration.

<span class="mw-page-title-main">H5N1 genetic structure</span>

H5N1 genetic structure is the molecular structure of the H5N1 virus's RNA.

<span class="mw-page-title-main">Virosome</span> Drug or vaccine delivery mechanism

A virosome is a drug or vaccine delivery mechanism consisting of unilamellar phospholipid membrane vesicle incorporating virus derived proteins to allow the virosomes to fuse with target cells. Viruses are infectious agents that can replicate in their host organism, however virosomes do not replicate. The properties that virosomes share with viruses are based on their structure; virosomes are essentially safely modified viral envelopes that contain the phospholipid membrane and surface glycoproteins. As a drug or vaccine delivery mechanism they are biologically compatible with many host organisms and are also biodegradable. The use of reconstituted virally derived proteins in the formation of the virosome allows for the utilization of what would otherwise be the immunogenic properties of a live-attenuated virus, but is instead a safely killed virus. A safely killed virus can serve as a promising vector because it won't cause infection and the viral structure allows the virosome to recognize specific components of its target cells.

<span class="mw-page-title-main">Neuraminic acid</span> Chemical compound

Neuraminic acid (5-amino-3,5-dideoxy-D-glycero-D-galacto-non-2-ulosonic acid) is an acidic (in particular ulosonic) amino sugar with a backbone formed by nine carbon atoms. Although 9-carbon sugars do not occur naturally, neuraminic acid may be regarded as a theoretical 9-carbon ketose in which the first link of the chain (the –CH2OH at position 1) is oxidised into a carboxyl group (–C(=O)OH), the hydroxyl group at position 3 is deoxidised (oxygen is removed from it), and the hydroxyl group at position 5 is substituted with an amino group (–NH2). Neuraminic acid may also be visualized as the product of an aldol-condensation of pyruvic acid and D-mannosamine (2-amino-2-deoxy-mannose).

<span class="mw-page-title-main">Influenza</span> Infectious disease, often just "the flu"

Influenza, commonly known as "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms begin from one to four days after exposure to the virus and last for about 2–8 days. Diarrhea and vomiting can occur, particularly in children. Influenza may progress to pneumonia, which can be caused by the virus or by a subsequent bacterial infection. Other complications of infection include acute respiratory distress syndrome, meningitis, encephalitis, and worsening of pre-existing health problems such as asthma and cardiovascular disease.

<span class="mw-page-title-main">Hemagglutinin</span>

In molecular biology, hemagglutinins are receptor-binding membrane fusion glycoproteins produced by viruses in the Paramyxoviridae family. Hemagglutinins are responsible for binding to receptors on red blood cells to initiate viral attachment and infection. The agglutination of red cells occurs when antibodies on one cell bind to those on others, causing amorphous aggregates of clumped cells.

<span class="mw-page-title-main">Hemagglutinin-neuraminidase</span>

Hemagglutinin-neuraminidase refers to a single viral protein that has both hemagglutinin and (endo) neuraminidase EC 3.2.1.18 activity. This is in contrast to the proteins found in influenza, where both functions exist but in two separate proteins. Its neuraminidase domain has the CAZy designation glycoside hydrolase family 83 (GH83).

<span class="mw-page-title-main">George Hirst (virologist)</span> American virologist and science administrator

George Keble Hirst, M.D. was an American virologist and science administrator who was among the first to study the molecular biology and genetics of animal viruses, especially influenza virus. He directed the Public Health Research Institute in New York City (1956–1981), and was also the founding editor-in-chief of Virology, the first English-language journal to focus on viruses. He is particularly known for inventing the hemagglutination assay, a simple method for quantifying viruses, and adapting it into the hemagglutination inhibition assay, which measures virus-specific antibodies in serum. He was the first to discover that viruses can contain enzymes, and the first to propose that virus genomes can consist of discontinuous segments. The New York Times described him as "a pioneer in molecular virology."

Neuraminidase inhibitors inhibit enzymatic activity of the enzyme neuraminidase (sialidase). These type of inhibitors have been introduced as anti-influenza drugs as they prevent the virus from exiting infected cells and thus stop further spreading of the virus. Neuraminidase inhibitors for human neuraminidase (hNEU) have the potential to be useful drugs as the enzyme plays a role in several signaling pathways in cells and is implicated in diseases such as diabetes and cancer.

<i>Influenza D virus</i> Species of virus

Influenza D virus is a species in the virus genus Deltainfluenzavirus, in the family Orthomyxoviridae, that causes influenza.

References

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  9. "EC 3.2.1.129".
  10. "EC 3.2.1.18".