Oseltamivir, mechanism

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.

Wang MZ, Tai CY, Mendel DB (2002) Mechanism by which mutations at His274 alter sensitivity of influenza a vims N1 neuraminidase to oseltamivir carboxylate and zanamivir. Antimicrob... 

Pharmacology 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 via inhibition of influenza virus neuraminidase with the possibility of alteration of virus particle aggregation and release. 

Influenza virus resistant to oseltamivir has not been found in naturally acquired isolates but has been isolated from influenza patients who have undergone treatment with this drug. These resistant strains contain mutations in the active site of neuraminidase and are generally less virulent and infective than nonresistant virus. In vitro passage of influenza virus in the presence of oseltamivir carboxylate can produce mutations in hemagglutinin that decrease the overall dependence of viral replication on neuraminidase however, the clinical relevance of this resistance mechanism is unknown. 

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. 

Mechanism of Action. Oseltamivir and zanamivir inhibit a specific enzyme (neuraminidase) that the influenza virus uses to complete its biosynthesis and release. By inhibiting this enzyme, these drugs impair a key step in viral replication, and reduce the ability of the virus to infect other respiratory cells. 

Oseltamivir and zanamivir are available for treatment of infections due to I influenza A and B. The mechanism of their antiviral action is inhibition of ... 

MECHANISMS OF ACTION AND RESISTANCE Influenza neuraminidase cleaves terminal sialic acid residues and destroys the receptors recognized by viral hemagglutinin, which are present on the ceU surface, in progeny virions, and in respiratory secretions, which is essential for virus release from infected cells. Oseltamivir carboxylate causes a conformational change in neuraminidase s active site and inhibits its activity, leading to viral aggregation at the ceU surface and reduced virus spread within the respiratory tract. 

I Amantadine blocks the attachment, penetration, and uncoating of influenza virus A zanamivir and oseltamivir inhibit influenza viruses A and B neuraminidase, promoting viral clumping and decreasing the chance of penetration. Ribavirin becomes phosphorylated and inhibits IMP dehydrogenase and RNA polymerase. It is used to treat respiratory syncytial virus, influenza A and B, Lassa fever. Hantavirus, and as an adjunct to alpha-interferons in hepatitis C. The mechanisms, clinical uses, and side effects of these drugs are considered. 

Probenecid markedly increased the AUC of the active metabolite of oseltamivir, but because of the large safety margin of oseltamivir, this increase is not considered to be clinically relevant. " Oseltamivir did not alter amoxicillin pharmacokinetics, and is therefore unlikely to interact with other renally secreted organic acids. Other drugs that are involved in the active anionic tubular secretion mechanism are also unlikely to interact. Cimetidine does not interact with oseltamivir, and other drugs that are inhibitors of the renal cationic secretion transport process are unlikely to interact. ... 

The mechanism for this interaction is not clear, but given the large number of people expected to be treated with oseltamivir for influenza, it is important to highlight it. 

T. Uchimaru, Y Hayashi, Chem. Eur. J. 2010, 16, 12616-12626. High-yielding synthesis of the anti-influenza neuranuni-dase inhibitor (-)-oseltamivir by two one-pot sequences, (c) K. Patora-Komisarska, M. Benohoud, H. Ishikawa, D. Seebach, Y. Hayashi, Helv. Chim. Acta 2011, 94, 719-745. Organocatalyzed Michael addition of aldehydes to nitro alkenes—generally accepted mechanism revisited and revised. 

Due to the transfer mechanism of TcTS analogous to those of sialidases [25] the prototype of sialidase inhibitors Neu5Ac2en 99 [57] was tested. Compound 99 as well as the potent influenza virus neuraminidase inhibitors zanamivir (Relenza, 100) and the active form of oseltamivir (Tamiflu, 101) with analogous structures of transition state were also of interest as potential inhibitors of TcTS. However, as determined for 99 the TcTS activity was inhibited with only Ki = 12.29 mM (Fig. 15) [33]. 

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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