Victrelis (boceprevir)
From Proteopedia
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 almost 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] Inhibition of this protease prevents viral replication in Hepatitis C virus infected cells.[4]
Mechanism of Action
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[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] In previous experiements, when any member of the catalytic triat was replaced by a different residue, cleavage at the NS3/NS4A, NS4A/NS4B, NS4B/NS5A, and NS5A/NS5B locations was inhibited.[3] Mammals also utilize serine proteases to cleave lengthy polypeptides.[6] 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.[7]
References
- ↑ Centers for Disease Control and Prevention. (2015). Viral hepatitis - hepatitis C information. Retrieved from http://www.cdc.gov/hepatitis/hcv/index.htm
- ↑ doi: https://dx.doi.org/10.1177/1756383X11436317
- ↑ 3.0 3.1 3.2
Structure of Hepatitis C Viral NS3 protease domain complexed with NS4A peptide and ketoamide SCH503034 (PDB code 2oc8)
Drag the structure with the mouse to rotate 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.<ref>Merck & Co., Inc. (n.d.) Highlights of prescribing information. Retrieved from https://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf</li> <li id="cite_note-Merck-3">[[#cite_ref-Merck_3-0|↑]]
== Structure of 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:<ref name ="Merck" /ref>
[[Image:Victrelis.png]]
Victrelis covalently, yet reversibly, binds to the NS3 serine protease at the <scene name='74/745993/Active_site_ser_139_2/1'>Ser139</scene> residue.<ref name ="Merck" /ref> When bound to the NS3 serine protease, Victrelis participates in <scene name='74/745993/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</li> <li id="cite_note-4">[[#cite_ref-4|↑]] Voet, D., Voet, J., Pratt, C. (2013). Fundamentals of biochemistry: life at the molecular level (4th ed.). Hoboken, New Jersey: John Wiley & Sons, Inc.</li> <li id="cite_note-5">[[#cite_ref-5|↑]] Voet, D., Voet, J., Pratt, C. (2013). Fundamentals of biochemistry: life at the molecular level (4th ed.). Hoboken, New Jersey: John Wiley & Sons, Inc.</li>
<li id="cite_note-6">[[#cite_ref-6|↑]] 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:[http://www.ncbi.nlm.nih.gov/pubmed/26357603 26357603] doi:[http://dx.doi.org/10.14218/JCTH.2013.002XX http://dx.doi.org/10.14218/JCTH.2013.002XX]</li></ol></ref>
