A-neuraminidase

The influenza virus possesses a neuraminidase that plays a key role in elution of newly synthesized progeny from infected cells. If this process is inhibited, spread of the vims is markedly diminished. Inhibitors of this enzyme are now available for use in treating patients with influenza. 

In order to exclusively measure binding of ligands to HA and to prevent binding to neuraminidase, a neuraminidase inhibitor Neu5Ac2en (Scheme 1) is added at high concentrations (10-20 mM) in all cases. Neuraminidase is also present on the surface of Influenza viruses and shares binding specificities with HA. 

Zanamivir (Relenza) is a neuraminidase inhibitor with activity against influenza A and B strains. Like oseltamivir, zanamivir is a reversible competitive antagonist of viral neuraminidase. It inhibits the release of progeny virus, causes viral aggregation at the cell surface, and impairs viral movement through respiratory secretions. Resistant variants with hemagglutinin and/or neuraminidase mutations have been produced in vivo however, clinical resistance to zanamivir is quite rare at present. 

L D. The conversion of penciclovir to its active form requires initial monophosphorylation by viral thymidine kinases, then conversion to its active triphosphate form by cellular enzymes. Thus, the concentration of penciclovir triphosphate is particularly high in cells infected with its target viruses (e.g., HSV, VZV, HBV). Foscarnet is a pyrophosphate analogue that does not require activation. Oseltamivir is a neuraminidase inhibitor that is con-... 

Gottschalk A. Neuraminidase the specific enzyme of influenza virus and vibrio cholerae. Biochem Biophys Acta 1957 23 645-646. 

Gottschalk A. Neuraminidase its substrate and mode of action. Adv Enzymol 1958 20 135-145. 

Liu C, Air GM. Selection and characterization of a neuraminidase-minus mutant of influenza virus and its rescue by cloned neuraminidase genes. Virol 1993 194 403 107. 

Alymova IV, Taylor G, Portner A. Neuraminidase inhibitors as antiviral agents. Curr Drug Targets Infect Disord. 2005 5 401-409. 

In order to prevent infection, for example, with an influenza virus, it is necessary to block at least one out of two of the substances present on its surface One of them is a neuraminidase, an enzyme that cleaves off sialic acid, and the other is a hemagglutinin, a sialic acid-specific lectin which aids the influenza viruses in docking onto oligosaccharides exposing sialic acid on the surface of host cells. Both compounds are prerequisite for the infection process. 

Several other important compounds found in the common aromatic amino acid pathway whose overproduction has been studied are shikimic acid (61) and, to a lesser extent, quinic acid (62) (Scheme 19.41).323 Both 61 and 62 are naturally occurring, highly functionalized carbocyclic rings with asymmetric centers, which can be used as starting material for the synthesis of GS4104 (63), a neuraminidase inhibitor discovered by Gilead Sciences and developed by Roche Pharmaceuticals under the trade name of Tamiflu .324 325 Manipulation of the aromatic amino acid pathway in E. coli has allowed for numerous strains to be assembled that produce both 61 and 62 as well as other intermediates.326 327 As reported by Chandran and co-workers, an E. coli strain has been constructed that synthesized 87 g/L (0.5m) of 61 in 36% (mol/mol) yield with a maximum productivity of 5.2 gL- lr1.328... 

In addition to the lipid bilayer, enveloped viruses generally have two or more distinct layers of protein that are organized across the membrane. Thus, most viruses have an outer layer of proteins, usually glycoproteins, which are anchored in the membrane as integral membrane proteins. These proteins function to attach the virion to target host cell receptors and facilitate the entry or fusion of the viral membrane with that of the host cell. In addition, some viruses also contain enzymatic activities associated with this outer layer of protein. For example, influenza virus carries with it a neuraminidase that is responsible for cleaving sialic acid residues on host cells. 

Zanamivir is a neuraminidase inhibitor which blocks entry of the influenza A and B viruses to target cells and the release of their progeny. It is administered as 5 mg of a dry powder twice daily in 5-day course via a special inhaler. Controlled trials have shown that the duration of symptoms is reduced from about 6 to 5 days, with a smaller reduction in the mean time taken to return to normal activities. In high-risk groups the reduction in duration of symptoms is a little greater, and fewer patients need antibiotics. 

Based on the lead compound BANA 113 42, which inhibits influenza A neuraminidase with a Ki of 2.5 p.M [91a,b], several novel 2-pyrrolidinone derivatives were designed. Whereas compound 43 (BANA 205) is a relatively weak inhibitor of influenza A and B neuraminidases, with IC50 values in the low micromolar range, compound 44 (BANA 206) is much more potent, with an IC50 value of 48 nM against influenza A neuraminidase. However, this compound is not as potent against influenza B virus sialidase [91d,e]. 

Interestingly, the comparison of the X-ray crystal structures of the complexes of influenza A neuraminidase with zanamivir 28 and BANA 113 42 revealed that, whUe the carboxylate and A-acetyl groups occupy the same subsites, the guanidino functionalities interact with the enzyme in different ways (Figure 16.14) [9Id]. 

Range of inhibitory potency against 15 different influenza A neuraminidases and 8 different influenza B neuraminidases... 

D The most appropriate therapy would be a neuraminidase inhibitor such as oseltamivir since amantadine and rimantadine do not cover influenza B. Treatment of influenza must be initiated within 48 hours of symptoms for maximum efficacy. Influenza vaccination is only effective for the prevention of influenza and not for symptomatic therapy. If this were influenza A and amantadine was chosen to treat this patient, dose adjustments would be necessary due to her renal insufficiency. She would also be at increased risk of CNS toxicity due to her age and possible accumulation of the drug due to her renal insufficiency. 

Zami 420 triletide. zanamivir [ban] (GR 121167X GG 167) is an JV-acetyIneuraminic acid derivative which acts as a neuraminidase (sialidase) inhibitor. It is an ANTIVIRAL that inhibits influenza virus replication, and has shown promise in phase III trials given by direct inhalation for limitation of the duration and severity of flu symptoms, zankiren hydrochloride zankiren. 

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