Oseltamivir

Better Known as: Tamiflu

• Marketed By: Gilead Sciences & Roche
• Major Indication: Influenza Infection
• Drug Class: Neuraminidase Inhibitor
• Date of FDA Approval (Patent Expiration): 1999 (2016)
• 2009 Sales: $3.1 Billion
• Importance: It has been proposed that the closer the inhibitor resembles the natural substrate (Sialic acid), the less likely they are to select drug-resistant mutant viruses. It was along this train of thought that Oseltamivir was designed. It was approved by the FDA just a few months after Zanamivir and quickly garnered 75% of the influenza market share. Many newer strains of Influenza, namely H1N1 have become resistant to Oseltamivir however, shifting market share back toward Zanamivir for which influenza has remained relatively unresistant toward.
• 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 hydrogen bonds to residues Tyr 406, Arg 371, and Arg 152 along with a number of . Of note, the of His 274 to Tyr confers resistance to Oseltamivir because the interaction between Tyr 274 & Glu 276, of Oseltamivir, increasing the K_i of Oseltamivir 265 fold. This is not the case with Zanamivir, which is barely impacted by the H274Y mutation (K_i increases by only 2 fold).^[2]

For additional details, including a morph of the induced fit of Tamiflu to avian influenza neuraminidase, see Avian Influenza Neuraminidase, Tamiflu and Relenza.

For References to Pharmacokinetic data, see: References