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Oseltamivir

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William Hutchens

on 10 October 2014

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Transcript of Oseltamivir

Neuraminidase
Hemagglutinin
INFLUENZA
Family:
Orthomyxoviridae
Varying symptoms from mild to severe
Good hygiene is first line of defense
Vaccines are used to minimize infection
Neuraminidase inhibitors are used to treat symptoms after infection

binds to the sialic acid when entering the cell
Hemagglutinin bound to Sialic acid
takes place
Virus travels to the exterior of the cell and then rebinds to sialic acid
Osel
tami
vir (
Tami
Flu)

Hydrolysis to active form
Biochemical Parameters
Drug Binding and Crystallization
Drug Resistance
Further Research
Testing to compensate for questionable clinical results
Post translational modifications
Outside factors on drug efficacy
Testing of alternate uses

The active site of the neuraminidase enzyme has a highly conserved amino acid sequence.
Oseltamivir hydrogen bonds to amino acid residues Arg117, Glu118, Asp150, Glu277, Arg292, and Arg 371 of the neuraminidase (N1).
Variability of biochemical parameters, IC50 and EC50, depending on assay performed.
Sialic Acid
Mutants have varied spatial orientation
Different electrostatic potential
Different hydrophobicity
Treatment frequency is directly related to resistance predominance
[1]
Oseltamivir incompletely inhibits viral replication
Resistance is increasing in many viral strains
H1N1
[2,3]
Seasonal flu
[4]
H3N2
[5]
Influenza B
[6]
UBC Public Affairs. Fighting flu; 2013.
Voet, D. Fundamentals of biochemistry: life at the molecular level; 4th ed.; Wiley: Hoboken, NJ, 2013.

Oseltamivir was first crystallized in 2000
Mohan, S.; McAtamney, S.; Haselhorst, T.; von Itzstein, M.; Pinto, B. M. J. Med. Chem. 2010, 53, 7377–7391.
Turner, R. B. Influenza http://www.merckmanuals.com/professional/infectious_diseases/respiratory_viruses/influenza.html.
Steinhauer, D. A. Virology 1999, 258, 1–20.
Varki A, Schauer R. Sialic Acids. In: Varki A, Cummings RD, Esko JD, et al., editors. Essentials of Glycobiology. 2nd edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2009. Chapter 14.
Wagner, R.; Matrosovich, M.; Klenk, H.-D. Rev. Med. Virol. 2002, 12, 159–166.
Wagner, R.; Matrosovich, M.; Klenk, H.-D. Rev. Med. Virol. 2002, 12, 159–166.
Schauer, R. In Advances in Carbohydrate Chemistry and Biochemistry; R. Stuart Tipson and Derek Horton, Ed.; Academic Press, 1982; Vol. Volume 40, pp. 131–234.
Schauer, R. In Advances in Carbohydrate Chemistry and Biochemistry; R. Stuart Tipson and Derek Horton, Ed.; Academic Press, 1982; Vol. Volume 40, pp. 131–234.
University of British Columbia. “New Flu Drug Stops Virus in Its Tracks.” UBC.ca. 21 Feb. 2013. Web. 6 Dec. 2013.

Davies, B. E. J. Antimicrob. Chemother. 2010, 65, ii5–ii10.
Swaine, Jon, and Smith, Rebecca. “Swine Flu: Online Pharmacies Report Huge Surge in Demand for Tamiflu.” The Telegraph 6 Dec. 2013 : n. pag. Print.

Tamiflu (oseltamivir phosphate) Information http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm107838.htm.
PDB: 2HT8
Oseltamivir binding to N8
Vergara-Jaque, A.; Poblete, H.; Lee, E. H.; Schulten, K.; González-Nilo, F.; Chipot, C. J. Chem. Inf. Model. 2012, 52, 2650–2656.
Open conformation of 150-loop in N1.
Closed conformation of 150-loop in N9.
1) Vergara-Jaque, A.; Poblete, H.; Lee, E. H.; Schulten, K.; González-Nilo, F.; Chipot, C. J. Chem. Inf. Model. 2012, 52, 2650–2656.
2) Storms, A. D.; Gubareva, L. V.; Su, S.; Wheeling, J. T.; Okomo-Adhiambo, M.; Pan, C.-Y.; Reisdorf, E.; St. George, K.; Myers, R.; Wotton, J. T.; Robinson, S.; Leader, B.; Thompson, M.; Shannon, M.; Klimov, A.; Fry, A. M.; for the US Antiviral Resistance Surveillance Working Group. Emerg. Infect. Dis. 2012, 18, 308–311.
3) 2007-08 U.S. Influenza Season Summary http://www.cdc.gov/flu/weekly/weeklyarchives2007-2008/07-08summary.htm.
4) CDC. Influenza Website of the Centers for Disease Control and Prevention (CDC) http://www.cdc.gov/flu/weekly/weeklyarchives2008-2009/08-09summary.htm (accessed Nov 26, 2013).
5) Kiso, M.; Mitamura, K.; Sakai-Tagawa, Y.; Shiraishi, K.; Kawakami, C.; Kimura, K.; Hayden, F. G.; Sugaya, N.; Kawaoka, Y. Lancet 2004, 364, 759–765.
6) Hatakeyama, S.; Sugaya, N.; Ito, M.; Yamazaki, M.; Ichikawa, M.; Kimura, K.; Kiso, M.; Shimizu, H.; Kawakami, C.; Koike, K.; Mitamura, K.; Kawaoka, Y. Jama J. Am. Med. Assoc. 2007, 297, 1435–1442.
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