Influenza A and B viruses

Sheu TG, Deyde VM, Okomo-Adhiambo M, Garten RJ, Xu X, Bright RA, Butler EN, Wallis TR, Klimov AI, Gubareva LV (2008) Surveillance for neuraminidase inhibitor resistance among human influenza A and B viruses circulating worldwide from 2004 to 2008, Antimicrob Agents Chemother 52 3284-3292,... 

Two neuraminidase inhibitors (oseltamivir carboxylate and zanamivir) are approved for prevention and treatment of infections with both influenza A and B viruses as discussed in chapter by Itzstein and Thomson, this volume. Oseltamivir carboxylate (OC) has gained most use because it can be taken orally, whereas the current formulation of zanamivir has to be inhaled. In addition, the WHO reconunends oseltamivir for treatment of clinically confirmed cases of H5N1 and for post-exposme prophylaxis to control recent H5N1 avian influenza outbreaks. 

Pharmacology Ribavirin is a synthetic nucleoside analog. It has antiviral activity in vitro against RSV, influenza A and B viruses, and herpes simplex virus. Pharmacokinetics ... 

Influenza treatment Treatment of uncomplicated acute illness caused by influenza A and B virus in adults and children 7 years of age and older who have been symptomatic for no more than 2 days. 

Zanamivir (2) is a potent competitive inhibitor of viral neuraminidase glycoprotein, which is essential in the infective cycle of both influenza A and B viruses. It inhibits a wide range of influenza A and B types in vitro as well as in vivo. The concentrations of inhibiting in vitro plaque formation of influenza A and B virus by 50% in Madin-Darby canine kidney (MDCK) cells were 0.004-0.014 p.mol/L in laboratory-passaged strains, and 0.002-16 p.mol/L in assays of clinical isolates. Due to its low bioavailability, it is delivered by inhalation via the Diskhaler , 10 mg twice daily, or intranasally 2-4 times daily for 5 days. After an intravenous dose of 1 -16 mg, the median elimination half-life was ti/2 = 7 h, the volume of distribution at steady state was Vdss = 16 L, and 90% of the dose was excreted unchanged in the urine. After intranasal and inhaled (dry powder) administration, maximum serum concentrations occurred within 2h and the terminal phase half-lives were 3.4 and 2.9 h, respectively. The bioavailabilities were 10 and 25%, respectively, and 20% after inhalation of zanamivir (2) by nebulizer. 

Zanamivir is indicated for treatment of uncomplicated acute influenza A and B virus in patients aged 7 and older. Treatment should be initiated no later than 2 days after the onset of symptoms. Zanamivir shortens the duration of illness by 1 to 1.5 days. It is also an effective prophylaxis against influenza however, the FDA has not approved this indication at the time of publication. 

Mechanism of Action A selective inhibitor of influenza virus neuraminidase, an enzyme essential for viral replication. Acts against both influenza A and B viruses. Therapeutic Effect Suppresses the spread of infect ion within the respiratory system and re-duces the duration of clinical symptoms. 

The majority of other modifications examined at the C-4 position of Neu5Ac2en involved A -alkylation or /V-acylation of 4-amino-4-deoxy-Neu5Ac-2en or modification of the guanidino substituent of Zanamivir. IV-Methylamino (22), A -al lyl (23), and Ar,Ar-dimethylamino (24) derivatives of amine 9 were effective inhibitors of NA from influenza A and B viruses (A) = 10 5-10 7M) though they showed diminished activity against a number of bacterial sialidases.57,65... 

Interest in modification of the C-5 substituent of Neu5Ac2en arose in the 1960s when a group of eighteen ALacyl-modified Neu5Ac2en derivatives were screened against influenza A and B virus sialidases.58 Among these compounds, trifluoro-acetamide 37 and difluoroacetamide 38 were identified as the first inhibitors of... 

Removal of the C-8 and C-9 hydroxy groups in order to produce a hydro-phobic side-chain, gave such derivatives as 67, which were evaluated against influenza A and B virus sialidases and used in a viral-replication assay.82 While these molecules displayed similar efficacy to the parent triol against influenza A virus sialidase, they were relatively ineffective against influenza B virus. 

A natural SP OKU-40 was extracted from the marine microalga Dinoflag-ellata and was found to inhibit the replication of HIV, RSV, influenza A and B viruses, measles virus, and parainfluenza viruses type 2 (PIV-2). However, it did not inhibit the replication of mumps virus or PIV-3 [98]. The action of negatively charged polysaccharides is not merely one of nonspecific inhibition of the binding of an enveloped virus to receptors. In fact, OKU-40 did not inhibit the binding of HIV or influenza A virus to the cell membrane, but it did inhibit the fusion of the membranes of HIV-infected MOLT-4 cells to those of uninfected cells and the fusion of the influenza A virus envelope to uninfected MDCK cells [99]. 

The currently most widely used class of antiviral inhibitors, however, has been developed by targeting the influenza virus sialidase, which is involved in the last stage of the life cycle of influenza A and B viruses [35], These inhibitors are discussed in detail in Section 17.7. 

X-ray crystal structure studies of influenza A/N2, A/N9, and B sialidases bound with a-Neu5Ac [66] show that the active site contains 18 invariant amino acid residues that either interact with the bound a-Neu5Ac or support these residues. These residues are conserved in all strains of influenza A and B viruses, suggesting their involvement in the enzymatic activity [65,66], The residues helped define the topology of the active site [66, 67], Of those conserved amino acids interacting with the substrate, many are polar, but there are also a number of nonpolar residues... 

In a structure-based drug-discovery programme in the field of influenza virus neuraminidase inhibitors, researchers at BioCryst Pharmaceuticals discovered aminocarbafuranose sialyl mimetic 89 as a very potent candidate against influenza A and B viruses [17]. To arrive at this highly substituted compound in a non-racemic format, the viable route of Scheme 14 was executed. 

Neuraminidase inhibitors prevent the release of influenza A and B viruses. Normally, the viral neuraminidase splits off N-acetyl-neuraminic (sialic) acid residues on the cellular surface coat, thereby enabling newly formed viral particles to be detached from the host cell. Zanamivir is given by inhalation oseltamivir is suitable for oral administration because it is an ester prodrug. Possible uses include treatment and prophylaxis of influenza virus infections. 

A number of C-4-substituted 2,3-didehydro derivatives show significant inhibition of influenza A and B virus sialidase. The C-4 amino derivative (163) was originally targeted as a potential inhibitor of influenza virus sialidase based on molecular modelling studies of the X-ray crystal structure of influenza A virus sialidase [189-191]. 

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. 

Monto AS, Fleming DM, Henry D, de Groot R, Makela M, Klein T, Elliott M, Keene ON, Man CY. Efficacy and safety of the neuraminidase inhibitor zanamivirin the treatment of influenza A and B virus infections. J Infect Dis 1999 180(2) 254-61. 

The MIST (Management of Influenza in the Southern Hemisphere Triahsts) Study Group. Randomised trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections. Lancet 1998 352(9144) 1877-81. 

Zanamivir and oseltamivir are neuraminidase inhibitors that are active against influenza A and B viruses. 

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