Victrelis (boceprevir)
From Proteopedia
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In previous experiments, when any member of the catalytic triad was replaced by a different residue, cleavage at the NS3/NS4A, NS4A/NS4B, NS4B/NS5A, and NS5A/NS5B locations was inhibited.<ref name="Line" /> By inhibiting the protease from cleaving the HCV at the NS3/NS4A location, the polyprotein is unable to be cleaved into smaller, functional proteins that compose replications machinery of HCV, thereby inhibiting viral replication.<ref name="Howe">doi:10.14218/JCTH.2013.002XX</ref> In addition to viruses, mammals also utilize serine proteases to cleave lengthy polypeptides that are involved in various essential mechanisms throughout the body.<ref name="Voet" /> Victrelis was testing among several different mammalian proteases, including those that are vital for blood clotting, digestion, and antibody neutralization, and it was found to be exclusively selective for inhibition of the NS3 serine protease of HCV only.<ref name="Howe" /> | In previous experiments, when any member of the catalytic triad was replaced by a different residue, cleavage at the NS3/NS4A, NS4A/NS4B, NS4B/NS5A, and NS5A/NS5B locations was inhibited.<ref name="Line" /> By inhibiting the protease from cleaving the HCV at the NS3/NS4A location, the polyprotein is unable to be cleaved into smaller, functional proteins that compose replications machinery of HCV, thereby inhibiting viral replication.<ref name="Howe">doi:10.14218/JCTH.2013.002XX</ref> In addition to viruses, mammals also utilize serine proteases to cleave lengthy polypeptides that are involved in various essential mechanisms throughout the body.<ref name="Voet" /> Victrelis was testing among several different mammalian proteases, including those that are vital for blood clotting, digestion, and antibody neutralization, and it was found to be exclusively selective for inhibition of the NS3 serine protease of HCV only.<ref name="Howe" /> | ||
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| - | Victrelis covalently, yet reversibly, binds to the NS3 serine protease at the <scene name='74/746128/Covalently_bound/3'>Ser139</scene> residue. When bound to the NS3 serine protease, Victrelis also participates in <scene name='74/746128/Hydrophobic_interactions/1'>hydrophobic interactions</scene> between the side chains of specific amino acid residues on the NS3 serine protease: Asp168, Arg155, Gly137, Gln41, and Ala156.<ref>doi:10.14218/JCTH.2013.002XX</ref> The reactive carbonyl group at the beta-carbon position, located two carbons away from the terminal amine group, of Victrelis is attacked by the nucleophilic oxygen in Ser139 to create a <scene name='74/746128/Covalently_bound/2'>covalent</scene> bond.<ref name="Merck" /><ref>doi:10.2210/pdb2oc8/pdb</ref> | ||
[[Image:Boceprevir bound to NS3 active site.jpg]] | [[Image:Boceprevir bound to NS3 active site.jpg]] | ||
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| - | Victrelis is a protease inhibitor. A protease is an enzyme that cleaves large polypeptides to create fragments that are small enough to be sequenced for effective replication.<ref name="Voet">Voet, D., Voet, J., Pratt, C. (2013). Fundamentals of biochemistry: life at the molecular level (4th ed.). Hoboken, New Jersey: John Wiley & Sons, Inc.</ref> Victrelis specifically inhibits the HCV NS3/4A protease, which is responsible for cleavage at four different sites along the polyprotein: NS3/NS4A, NS4A/NS4B, NS4B/NS5A, and NS5A/NS5B.<ref name="Line" /> By inhibiting cleavage at these sites, smaller protein fragments are unable to be produced, causing a halt in RNA replication due to the large size of the polyproteins. The active ingredient in Victrelis, boceprevir, covalently binds to the active site serine <scene name='74/746128/Covalently_bound/1'>(Ser139)</scene> in the NS3 protease. The nucleophilic oxygen in the hydroxyl of the Ser139 group binds to the second carbon from the primary amine group, also known as the beta-carbon. When unbound, Ser139 forms hydrogen interactions with both His57 and Asp81 to create a <scene name='74/746128/Catalytic_triad/1'>catalytic triad</scene><ref name="Line" />, and Gly137 to create an oxyanion hole.<ref name="Line" /> The oxyanion hole is critical for for stabilizing negative charges of protease intermediates.<ref>Brandt, Mark. (2016). Enzyme mechanisms. Retrieved from https://www.rose-hulman.edu/~brandt/Chem330/Enzyme_mech_examples.pdf</ref> In previous experiments, when any member of the catalytic triad was replaced by a different residue, cleavage at the NS3/NS4A, NS4A/NS4B, NS4B/NS5A, and NS5A/NS5B locations was inhibited.<ref name="Line" /> By inhibiting the protease from cleaving the HCV at the NS3/NS4A location, the polyprotein is unable to be cleaved into smaller, functional proteins that compose replication machinery of HCV, thereby inhibiting viral replication.<ref>doi:10.14218/JCTH.2013.002XX</ref> In addition to viruses, mammals also utilize serine proteases to cleave lengthy polypeptides.<ref name="Voet" /> Victrelis was tested among several different mammalian proteases, including those that are vital for blood clotting, digestion, and antibody neutralization, and it was found to be exclusively selective for inhibition of the NS3 serine protease of HCV only.<ref>doi:10.14218/JCTH.2013.002XX</ref> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 22:32, 5 December 2016
Contents |
Hepatitis C Virus
The Hepatitis C virus (HCV) is a blood-borne, single stranded RNA virus. [1] Chronic Hepatitis C infection is a leading cause of mortality and morbidity across the globe, affecting between 130-170 million people. [2] The genome of HCV encodes a polyprotein precursor of approximately 3,000 amino acids, which are cleaved into 10 proteins by various proteases, one of which is the non-structural protein 3 (NS3) serine protease.[3]
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Victrelis
Victrelis (boceprevir) is an antiviral Hepatitis C medication approved by the United States Food and Drug Administration in 2011. Victrelis is an inhibitor of the NS3 serine protease. Inhibition of this protease prevents viral replication in Hepatitis C virus infected cells. [4]
Structure of Unbound Victrelis
The active ingredient in Victrelis, boceprevir, is an equal mixture of two diastereomers made of entirely organic molecules. The molecular formula is C27H45N5O5, and the molecular weight is 519.8 grams/mole. The structural formula is as follows: [4]
RNA Replication
Structure of Bound Victrelis & Mechanism of Action
Victrelis is a protease inhibitor.[4] A protease is an enzyme that cleaves large polypeptides to create fragments that are small enough to be sequenced for effective replication.[5] Victrelis specifically inhibits the HCV NS3/4A protease, which is responsible for cleavage at four different sites along the polyprotein: NS3/NS4A, NS4A/NS4B, NS4B/NS5A, and NS5A/NS5B.[3] By inhibiting cleavage at these sites, smaller protein fragments are unable to be produced, causing a halt in RNA replication due to the large size of the polyproteins. The active ingredient in Victrelis, boceprevir, covalently binds to the active site serine in the NS3 protease.[3] The nucleophilic oxygen in the hydroxyl of the Ser139 group binds to Victrelis at the carbon of the carbonyl group located two carbons away from the terminal amine.[3]
The Ser139 residue of the NS3 serine protease participates in the formation of two critical structures for serine protease function: the catalytic triad and the oxyanion hole.[3] The catalytic triad is formed through interactions with Ser139, His57, and Asp81.[3] Asp81 stabilizes His57 after His57 deprotonates the hydroxyl group of Ser139.[3] These three residues form a triad through hydrogen bonding interactions.[3] The oxyanion hole is formed when Ser139 hydrogen bonds to Gly137.[3] The oxyanion structure is crucial to stabilizing the negative charges of protease intermediates.[6]
Victrelis covalently, yet reversibly, binds to the NS3 protease at the residue, thereby prohibiting interactions between the oxyanion hole and negative intermediates, as well as the catalytic triad and substrates.[3] When bound to the NS3 serine protease, Victrelis also participates in between the side chains of specific amino acid residues on the NS3 serine protease: Gln41, Gly137, Arg155, Ala156, and Asp168.[3] The reactive carbonyl group at the beta-carbon position, located two carbons away from the terminal amine group, of Victrelis is attacked by the nucleophilic oxygen in Ser139 to create a bond.[7]
In previous experiments, when any member of the catalytic triad was replaced by a different residue, cleavage at the NS3/NS4A, NS4A/NS4B, NS4B/NS5A, and NS5A/NS5B locations was inhibited.[3] By inhibiting the protease from cleaving the HCV at the NS3/NS4A location, the polyprotein is unable to be cleaved into smaller, functional proteins that compose replications machinery of HCV, thereby inhibiting viral replication.[8] In addition to viruses, mammals also utilize serine proteases to cleave lengthy polypeptides that are involved in various essential mechanisms throughout the body.[5] Victrelis was testing among several different mammalian proteases, including those that are vital for blood clotting, digestion, and antibody neutralization, and it was found to be exclusively selective for inhibition of the NS3 serine protease of HCV only.[8]
References
- ↑ Centers for Disease Control and Prevention. (2015). Viral hepatitis - hepatitis C information. Retrieved from http://www.cdc.gov/hepatitis/hcv/index.htm
- ↑ Averhoff FM, Glass N, Holtzman D. Global burden of hepatitis C: considerations for healthcare providers in the United States. Clin Infect Dis. 2012 Jul;55 Suppl 1:S10-5. doi: 10.1093/cid/cis361. PMID:22715208 doi:http://dx.doi.org/10.1093/cid/cis361
- ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 Lin C. HCV NS3-4A Serine Protease PMID:21250386
- ↑ 4.0 4.1 4.2 Merck & Co., Inc. (n.d.) Highlights of prescribing information. Retrieved from https://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf
- ↑ Cite error: Invalid
<ref>tag; no text was provided for refs namedVoet - ↑ Brandt, Mark. (2016). Enzyme mechanisms. Retrieved from https://www.rose-hulman.edu/~brandt/Chem330/Enzyme_mech_examples.pdf
- ↑ doi: https://dx.doi.org/10.2210/pdb2oc8/pdb
- ↑ 8.0 8.1 Howe AY, Venkatraman S. The Discovery and Development of Boceprevir: A Novel, First-generation Inhibitor of the Hepatitis C Virus NS3/4A Serine Protease. J Clin Transl Hepatol. 2013 Sep;1(1):22-32. doi: 10.14218/JCTH.2013.002XX. Epub, 2013 Sep 15. PMID:26357603 doi:http://dx.doi.org/10.14218/JCTH.2013.002XX
