Oseltamivir
From Proteopedia
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===Mechanism of Action=== | ===Mechanism of Action=== | ||
| - | Viral [[Neuraminidase]] is one of two major glycoproteins found on the surface of [[influenza]] viral membranes, the other being [[hemagglutinin]]. When the influenza virus infects a host cell, it attaches itself to the host via hemagglutinin interactions with host glycans, facilitating the fusion of host endosomal membrane with the viral membrane. After the virus has successfully infected the host and replicated extensively, the viral cargo is released from the cell via budding. During the budding process, the viral cargo is attached to the host cell once again via hemagglutinins, allowing the viral particle to form completely. Once the viral particle is formed, Neuraminidase cleaves the terminal sialic (neuraminic) acid residues from the glycan structures on the surface of the infected cell, breaking the hemmaglutinin-glycan interaction and promoting release of the viral particle to infect other cells. Oseltamivir functions by inhibiting the function of <scene name='Oseltamivir/N1_neuraminidase/1'>viral neuraminidase</scene>, preventing the viral particle from being released from the infected cell, thus limiting the severity and spread of [[viral infections]].<ref>PMID:1438172</ref> It binds to the active site of Neuraminidase causing dramatic conformational adjustments which render the protein non-functional. This prevents neuraminidase from cleaving the hemmaglutinin-glycan tethers and releasing the viral cargo after viral replication. Oseltamivir binding causes the <scene name=' | + | Viral [[Neuraminidase]] is one of two major glycoproteins found on the surface of [[influenza]] viral membranes, the other being [[hemagglutinin]]. When the influenza virus infects a host cell, it attaches itself to the host via hemagglutinin interactions with host glycans, facilitating the fusion of host endosomal membrane with the viral membrane. After the virus has successfully infected the host and replicated extensively, the viral cargo is released from the cell via budding. During the budding process, the viral cargo is attached to the host cell once again via hemagglutinins, allowing the viral particle to form completely. Once the viral particle is formed, Neuraminidase cleaves the terminal sialic (neuraminic) acid residues from the glycan structures on the surface of the infected cell, breaking the hemmaglutinin-glycan interaction and promoting release of the viral particle to infect other cells. Oseltamivir is a prodrug which is rapidly metabolized into its active form. It functions by inhibiting the function of <scene name='Oseltamivir/N1_neuraminidase/1'>viral neuraminidase</scene>, preventing the viral particle from being released from the infected cell, thus limiting the severity and spread of [[viral infections]].<ref>PMID:1438172</ref> It binds to the active site of Neuraminidase causing dramatic conformational adjustments which render the protein non-functional. This prevents neuraminidase from cleaving the hemmaglutinin-glycan tethers and releasing the viral cargo after viral replication. Oseltamivir binding causes the <scene name='Oseltamivir/150_loops/1'>so-called 150 loop</scene> (residues 147-151) to shift, <scene name='Oseltamivir/Actve/2'>covering part of the binding pocket</scene>, while Oseltamivir situates itself <scene name='Oseltamivir/Os_ac/1'>firmly within the active site</scene> using significant hydrogen bonding <scene name='___'>interactions with residues</scene> __. Of note, <scene name='___'>well known mutation</scene> of His 274 to Tyr confers resistance to Oseltamivir because ___. This is not the case with [[Zanamivir]], which does not inetract with His 274. |
===Pharmacokinetics=== | ===Pharmacokinetics=== | ||
Revision as of 14:30, 12 December 2010
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Better Known as: Tamiflu
- Marketed By: Gilead Sciences & Roche
- Major Indication: Influenza Infection
- Drug Class: Neuraminidase Inhibitor
- Date of FDA Approval: 1999 (2016)
- 2009 Sales: $3.1 Billion
- Importance:
- See Pharmaceutical Drugs for more information about other drugs and diseases.
Mechanism of Action
Viral Neuraminidase is one of two major glycoproteins found on the surface of influenza viral membranes, the other being hemagglutinin. When the influenza virus infects a host cell, it attaches itself to the host via hemagglutinin interactions with host glycans, facilitating the fusion of host endosomal membrane with the viral membrane. After the virus has successfully infected the host and replicated extensively, the viral cargo is released from the cell via budding. During the budding process, the viral cargo is attached to the host cell once again via hemagglutinins, allowing the viral particle to form completely. Once the viral particle is formed, Neuraminidase cleaves the terminal sialic (neuraminic) acid residues from the glycan structures on the surface of the infected cell, breaking the hemmaglutinin-glycan interaction and promoting release of the viral particle to infect other cells. Oseltamivir is a prodrug which is rapidly metabolized into its active form. It functions by inhibiting the function of , preventing the viral particle from being released from the infected cell, thus limiting the severity and spread of viral infections.[1] It binds to the active site of Neuraminidase causing dramatic conformational adjustments which render the protein non-functional. This prevents neuraminidase from cleaving the hemmaglutinin-glycan tethers and releasing the viral cargo after viral replication. Oseltamivir binding causes the (residues 147-151) to shift, , while Oseltamivir situates itself using significant hydrogen bonding __. Of note, of His 274 to Tyr confers resistance to Oseltamivir because ___. This is not the case with Zanamivir, which does not inetract with His 274.
Pharmacokinetics
For References to Pharmacokinetic data, see: References |
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References
- ↑ Varghese JN, McKimm-Breschkin JL, Caldwell JB, Kortt AA, Colman PM. The structure of the complex between influenza virus neuraminidase and sialic acid, the viral receptor. Proteins. 1992 Nov;14(3):327-32. PMID:1438172 doi:http://dx.doi.org/10.1002/prot.340140302
