Oseltamivir antiviral activity

Currently, two classes of drugs are available with antiviral activity against influenza viruses inhibitors of the ion channel activity of the M2 membrane protein, amantadine and rimantadine, and the neuraminidase inhibitors oseltamivir, and zanamivir. H5N1 viruses isolated from poultry and humans in Thailand and Viet Nam in 2004 invariably showed an amantadine-resistance indicating that amantadine treatment is not an option during the ongoing outb-treak in South-East Asia. 

Several carbocylic analogues of zanamivir that have been developed subsequently that display the same antiviral activity as zanamivir. The importance of the first of these, oseltamivir, more familiarly known as Tamiflu , has attracted the attention of academic chemists. Departing briefly from the organizing principle of this book. 

Oseltamivir phosphate is an ethyl ester prodrug that lacks antiviral activity. Oseltamivir carboxylate has an antiviral spectrum and potency similar to that of zanamivir. It inhibits amantadine- and rimantadine-resistant influenza A viruses and some zanamivir-resistant variants. 

CHEMISTRY AND ANTIVIRAL ACTIVITY Oseltamivir carboxylate [(3R, 4R, 55)-4-acetylamino-5-amino-3(l-ethylpropoxyl)-l-cyclohexene-l-carboxylic acid] is a sialic acid analog that potently inhibits influenza vims neuraminidases. 

CHEMISTRY AND ANTIVIRAL ACTIVITY Zanamivir (4-guanidino-2,4-dideoxy-2, 3-dehydro-/V-acetyl neuraminic acid) is a siaMc acid analog that potently and specifically inhibits the neuraminidases of influenza A and B viruses. Depending on the strain, zanamivir competitively inhibits influenza neuraminidase activity but affects neuraminidases from other pathogens and mammalian sources only at much higher concentrations. Zanamivir inhibits in vitro replication of influenza A and B viruses, including amantadine- and rimantadine-resistant strains and several oseltamivir-resistant variants. 

The manufacturers advise that antivirals active against influenza such as oseltamivir and rimantadine should not be given until 2 weeks after the administration of live influenza virus vaccines, and that these vaccines should not be given until 48 hours after stopping the antiviraL This is because of the theoretical concern that these antiviral drugs will inhibit replication of live vaccine virus, and therefore reduce its effect. Note that most influenza vaccines are inactivated (split virion or surface antigen), and that these would not be expected to be affected by antivirals active against influenza. 

Antacids do not affect the pharmacokinetics of oseltamivir, and there is no pharmacokinetic interaction between aspirin or paracetamol (acetaminophen) and oseltamivir. Aspirin and a variety of other drugs used for influenza management do not affect the antiviral activity of zanamivir in vitro. 

All compounds were assayed against both herpes simplex virus-1 (HSV-1) and human parainfluenza virus type 3 (PI-3) by using Madin Darby Bovine Kidney and Vero cell lines with the aim to capture structure relationship in each of the compounds. Acyclovir and oseltamivir were used as control agents. Correlation between toxicity on uninfected cells (Vero, MDBK) and antiviral activity of the synthesis compounds were determined in the same microtiter plate. The results of the antiviral study are presented in Table 2. 

Figure 4.18 The structure of Tamiflu (oseltamivir phosphate), an antiviral agent active against type A influenza, and a molecular model of its minimum-energy conformation, as calculated by molecular mechanics.

Abed Y, Nehmd B, Baz M, Boivin G (2008) Activity of the neuraminidase inhibitor A-315675 against oseltamivir-resistant influenza neuraminidases of N1 and N2 subtypes. Antiviral Res 77 163-166... 

Ives JA, Carr JA, Mendel DB, Tai CY, Lambkin R, Kelly L, Oxford JS, Hayden FG, Roberts NA (2002) The H274Y mutation in the influenza A/HINI neuraminidase active site following oseltamivir phosphate treatment leave virus severely compromised both in vitro and in vivo. Antiviral Res 55 307-317... 

The neuramidase inhibitor oseltamivir phosphate was discovered by Gilead Sciences and developed by Roche Pharmaceuticals under the name of Tamiflu (Scheme 5.13) to be used as an orally active antiviral compound for prevention and treatment of influenza infections. Because of the recent emergence of the avian flu, the demand for Tamiflu has gained momentum. Two industrially feasible syntheses are known, starting from (—)-shikimic acid and (—)-quinic acid, respectively (Scheme 5.13) [45]. 

A. Oseltamivir inhibits neuraminidase, an enzyme that cleaves neuraminic acid from oligosaccharides. Neuraminidase activity aids the movement of viral particles through neuraminic acid-rich respiratory secretions and is required for the release of progeny virions. Inhibition of viral DNA polymerase is the mechanism of action of nucleoside analogue antiviral drugs. Interferons do stimulate the JAK-STAT signaling pathway but do not stimulate proliferation of immune cells. Ribavirin inhibits GTP synthesis, and the antiretroviral protease inhibitors (e.g., ritonavir) inhibit HIV protease. 

Although antiviral drugs available for influenza have activity against influenza A, many or most of the circulating strains of avian H5N1, as well as the HI and H3 strains causing seasonal influenza in the United States, are resistant to the adamantane agents. Resistance to oseltamivir has also increased dramatically. 

Zhu HJ, Markowitz JS. Activation of the antiviral prodrug oseltamivir is impaired by two newly identified carboxylesterase 1 variants. Drug Metab Dispos 2009 37... 

Oseltamivir is an antiviral drug whose phosphate salt is marketed by Hoffmann-La Roche (Basel, Switzerland) under the trade name Tamiflu sold as capsules containing 30 mg, 45 mg, or 75 mg oseltamivir for oral use. It is indicated for the treatment of uncomplicated acute infection caused by influenza A or B virus in patients older than 1 year of age who have been symptomatic for no more than 2 days. Oseltamivir is an ethyl ester prodrug requiring ester hydrolysis for conversion to the active form, oseltamivir carboxylate. The proposed mechanism of action of oseltamivir is inhibition of influenza virus neuraminidase with the possibility of alteration of virus particle aggregation and release. ... 

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