Oseltamivir - Revision history

Alexander Berchansky at 09:17, 14 January 2024

Alexander Berchansky — Sun, 14 Jan 2024 09:17:07 GMT

←Older revision		Revision as of 09:17, 14 January 2024
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-	<~~applet~~ load="" size=~~"480" color~~=~~"" frame="true" spin="on" Scene ="Oseltamivir/Oseltamivir/1" align="~~right" caption="Oseltamivir, better known as Tamiflu, ([[2hu0]])"/>	+	<StructureSection load='' size='340' side='right' caption='Oseltamivir, better known as Tamiflu, ([[2hu0]])' scene='Oseltamivir/Oseltamivir/1'>
	===Better Known as: Tamiflu===		===Better Known as: Tamiflu===
	* Marketed By: Gilead Sciences & Roche		* Marketed By: Gilead Sciences & Roche
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	For additional details, including a morph of the induced fit of Tamiflu to avian influenza neuraminidase, see [[Avian Influenza Neuraminidase, Tamiflu and Relenza]].		For additional details, including a morph of the induced fit of Tamiflu to avian influenza neuraminidase, see [[Avian Influenza Neuraminidase, Tamiflu and Relenza]].
-		+	</StructureSection>
	===Pharmacokinetics===		===Pharmacokinetics===
	<table style="background: cellspacing="0px" align="" cellpadding="0px" width="52%">		<table style="background: cellspacing="0px" align="" cellpadding="0px" width="52%">

Eric Martz: /* References */

Eric Martz — Tue, 01 May 2012 21:43:42 GMT

References

←Older revision		Revision as of 21:43, 1 May 2012
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	</tr>		</tr>
	</table>		</table>
		+
		+	===See Also===
		+
		+	* [[Avian Influenza Neuraminidase, Tamiflu and Relenza]]

	===References===		===References===
	<references/>		<references/>
	__NOTOC__		__NOTOC__

Eric Martz: /* Mechanism of Action */

Eric Martz — Tue, 01 May 2012 21:43:08 GMT

Mechanism of Action

←Older revision		Revision as of 21:43, 1 May 2012
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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 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 hydrogen bonds to residues Tyr 406, Arg 371, and Arg 152 along with a number of <scene name='Oseltamivir/Bound/1'>other interactions</scene>. Of note, the <scene name='Oseltamivir/His/1'>well known mutation</scene> of His 274 to Tyr confers resistance to Oseltamivir because the interaction between Tyr 274 & Glu 276, <scene name='Oseltamivir/His/2'>shifts Glu 276 into the binding site</scene> of Oseltamivir, increasing the K<sub>i</sub> of Oseltamivir 265 fold. This is not the case with [[Zanamivir]], which is barely impacted by the H274Y mutation (K<sub>i</sub> increases by only 2 fold).<ref>PMID: 18480754</ref>		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 hydrogen bonds to residues Tyr 406, Arg 371, and Arg 152 along with a number of <scene name='Oseltamivir/Bound/1'>other interactions</scene>. Of note, the <scene name='Oseltamivir/His/1'>well known mutation</scene> of His 274 to Tyr confers resistance to Oseltamivir because the interaction between Tyr 274 & Glu 276, <scene name='Oseltamivir/His/2'>shifts Glu 276 into the binding site</scene> of Oseltamivir, increasing the K<sub>i</sub> of Oseltamivir 265 fold. This is not the case with [[Zanamivir]], which is barely impacted by the H274Y mutation (K<sub>i</sub> increases by only 2 fold).<ref>PMID: 18480754</ref>
		+
		+	For additional details, including a morph of the induced fit of Tamiflu to avian influenza neuraminidase, see [[Avian Influenza Neuraminidase, Tamiflu and Relenza]].

	===Pharmacokinetics===		===Pharmacokinetics===

Eric Martz at 21:42, 1 May 2012

Eric Martz — Tue, 01 May 2012 21:42:16 GMT

←Older revision		Revision as of 21:42, 1 May 2012
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	===References===		===References===
	<references/>		<references/>
-	__NOEDITSECTION__
	__NOTOC__		__NOTOC__

David Canner at 07:33, 14 December 2010

David Canner — Tue, 14 Dec 2010 07:33:08 GMT

←Older revision		Revision as of 07:33, 14 December 2010
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	* Date of FDA Approval (Patent Expiration): 1999 (2016)		* Date of FDA Approval (Patent Expiration): 1999 (2016)
	* 2009 Sales: $3.1 Billion		* 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 [User:Michael Strong/H1N1\|H1N1]] have become resistant to Oseltamivir however, shifting market share back toward Zanamivir for which influenza has remained relatively unresistant toward.	+	* 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 [[User:Michael Strong/H1N1\|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.		* See [[Pharmaceutical Drugs]] for more information about other drugs and diseases.

David Canner at 07:32, 14 December 2010

David Canner — Tue, 14 Dec 2010 07:32:58 GMT

←Older revision		Revision as of 07:32, 14 December 2010
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	* Major Indication: [[Influenza]] Infection		* Major Indication: [[Influenza]] Infection
	* Drug Class: [[Neuraminidase]] Inhibitor		* Drug Class: [[Neuraminidase]] Inhibitor
-	* Date of FDA Approval: 1999 (2016)	+	* Date of FDA Approval (Patent Expiration): 1999 (2016)
	* 2009 Sales: $3.1 Billion		* 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 [User:Michael Strong/H1N1\|H1N1]] have become resistant to Oseltamivir however, shifting market share back toward Zanamivir for which influenza has remained relatively unresistant toward.		* 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 [User:Michael Strong/H1N1\|H1N1]] have become resistant to Oseltamivir however, shifting market share back toward Zanamivir for which influenza has remained relatively unresistant toward.

David Canner at 15:05, 12 December 2010

David Canner — Sun, 12 Dec 2010 15:05:17 GMT

←Older revision		Revision as of 15:05, 12 December 2010
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	===Pharmacokinetics===		===Pharmacokinetics===
-	<table style="background: cellspacing="0px" align="" cellpadding="0px" width="42%">	+	<table style="background: cellspacing="0px" align="" cellpadding="0px" width="52%">
	<tr>		<tr>
	<td style="width:100%; vertical-align:top;border-width:0px; border-style:inset">		<td style="width:100%; vertical-align:top;border-width:0px; border-style:inset">

David Canner at 15:04, 12 December 2010

David Canner — Sun, 12 Dec 2010 15:04:47 GMT

←Older revision		Revision as of 15:04, 12 December 2010
Line 6:		Line 6:
	* Date of FDA Approval: 1999 (2016)		* Date of FDA Approval: 1999 (2016)
	* 2009 Sales: $3.1 Billion		* 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.	+	* 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 [User:Michael Strong/H1N1\|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.		* See [[Pharmaceutical Drugs]] for more information about other drugs and diseases.

David Canner at 15:03, 12 December 2010

David Canner — Sun, 12 Dec 2010 15:03:41 GMT

←Older revision		Revision as of 15:03, 12 December 2010
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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 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 hydrogen bonds to residues Tyr 406, Arg 371, and Arg 152 along with a number of <scene name='Oseltamivir/Bound/1'>other interactions</scene>. Of note, the <scene name='Oseltamivir/His/1'>well known mutation</scene> of His 274 to Tyr confers resistance to Oseltamivir because the interaction between Tyr 274 & Glu 276, shifts Glu 276 into the binding site of Oseltamivir, increasing the K<sub>i</sub> of Oseltamivir 265 fold. This is not the case with [[Zanamivir]], which is barely impacted by the H274Y mutation (K<sub>i</sub> increases by only 2 fold).<ref>PMID: 18480754</ref>	+	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 hydrogen bonds to residues Tyr 406, Arg 371, and Arg 152 along with a number of <scene name='Oseltamivir/Bound/1'>other interactions</scene>. Of note, the <scene name='Oseltamivir/His/1'>well known mutation</scene> of His 274 to Tyr confers resistance to Oseltamivir because the interaction between Tyr 274 & Glu 276, <scene name='Oseltamivir/His/2'>shifts Glu 276 into the binding site</scene> of Oseltamivir, increasing the K<sub>i</sub> of Oseltamivir 265 fold. This is not the case with [[Zanamivir]], which is barely impacted by the H274Y mutation (K<sub>i</sub> increases by only 2 fold).<ref>PMID: 18480754</ref>

	===Pharmacokinetics===		===Pharmacokinetics===

David Canner at 15:02, 12 December 2010

David Canner — Sun, 12 Dec 2010 15:02:31 GMT

←Older revision		Revision as of 15:02, 12 December 2010
Line 6:		Line 6:
	* Date of FDA Approval: 1999 (2016)		* Date of FDA Approval: 1999 (2016)
	* 2009 Sales: $3.1 Billion		* 2009 Sales: $3.1 Billion
-	* Importance:	+	* 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.		* See [[Pharmaceutical Drugs]] for more information about other drugs and diseases.

	===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 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~~.	+	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 hydrogen bonds to residues Tyr 406, Arg 371, and Arg 152 along with a number of <scene name='Oseltamivir/Bound/1'>other interactions</scene>. Of note, the <scene name='Oseltamivir/His/1'>well known mutation</scene> of His 274 to Tyr confers resistance to Oseltamivir because the interaction between Tyr 274 & Glu 276, shifts Glu 276 into the binding site of Oseltamivir, increasing the K<sub>i</sub> of Oseltamivir 265 fold. This is not the case with [[Zanamivir]], which is barely impacted by the H274Y mutation (K<sub>i</sub> increases by only 2 fold).<ref>PMID: 18480754</ref>

	===Pharmacokinetics===		===Pharmacokinetics===