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Pathway Description
Boceprevir Action Pathway
Homo sapiens
Drug Action Pathway
Boceprevir is a hepatitis C virus NS3/4A protease inhibitor used in combination with other medications to treat chronic hepatitis C genotype 1 infection.
Hepatitis C virus lipoviroparticles enter target hepatocytes via receptor-mediated endocytosis. The lipoviroparticles attach to LDL-R and SR-B1, and then the virus binds to CD81 and subsequently claudin-1 and occludin, which mediate the late steps of viral entry. The virus is internalized by clathrin-dependent endocytosis. RNA is released from the mature Hepatitis C virion and translated at the rough endoplasmic reticulum into a single Genome polyprotein.
Boceprevir accumulates in the liver after uptake into hepatocytes via solute carrier organic anion transporter family member 1B1. Boceprevir inhibits NS3/4A protease, which is an enzyme that cleaves the heptatitis C virus polyprotein downstream of the NS3 proteolytic site, which generates nonstructural proteins NS3, NS4A, NS4B, NS5A, and NS5B. These proteins are required in viral RNA replication, therefore because of the inhibition of their formation, RNA replication cannot occur. Because RNA replication does not occur, the mature virion is unable to form.
References
Boceprevir Pathway References
Herker E, Ott M: Unique ties between hepatitis C virus replication and intracellular lipids. Trends Endocrinol Metab. 2011 Jun;22(6):241-8. doi: 10.1016/j.tem.2011.03.004. Epub 2011 Apr 15.
Pubmed: 21497514
Ahmed A, Felmlee DJ: Mechanisms of Hepatitis C Viral Resistance to Direct Acting Antivirals. Viruses. 2015 Dec 18;7(12):6716-29. doi: 10.3390/v7122968.
Pubmed: 26694454
Ali A, Aydin C, Gildemeister R, Romano KP, Cao H, Ozen A, Soumana D, Newton A, Petropoulos CJ, Huang W, Schiffer CA: Evaluating the role of macrocycles in the susceptibility of hepatitis C virus NS3/4A protease inhibitors to drug resistance. ACS Chem Biol. 2013 Jul 19;8(7):1469-78. doi: 10.1021/cb400100g. Epub 2013 May 1.
Pubmed: 23594083
Kiser JJ, Flexner C: Direct-acting antiviral agents for hepatitis C virus infection. Annu Rev Pharmacol Toxicol. 2013;53:427-49. doi: 10.1146/annurev-pharmtox-011112-140254. Epub 2012 Nov 5.
Pubmed: 23140245
Wilby KJ, Partovi N, Ford JA, Greanya E, Yoshida EM: Review of boceprevir and telaprevir for the treatment of chronic hepatitis C. Can J Gastroenterol. 2012 Apr;26(4):205-10. doi: 10.1155/2012/751057.
Pubmed: 22506260
Malcolm BA, Liu R, Lahser F, Agrawal S, Belanger B, Butkiewicz N, Chase R, Gheyas F, Hart A, Hesk D, Ingravallo P, Jiang C, Kong R, Lu J, Pichardo J, Prongay A, Skelton A, Tong X, Venkatraman S, Xia E, Girijavallabhan V, Njoroge FG: SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells. Antimicrob Agents Chemother. 2006 Mar;50(3):1013-20. doi: 10.1128/AAC.50.3.1013-1020.2006.
Pubmed: 16495264
Bagaglio S, Uberti-Foppa C, Morsica G: Resistance Mechanisms in Hepatitis C Virus: implications for Direct-Acting Antiviral Use. Drugs. 2017 Jul;77(10):1043-1055. doi: 10.1007/s40265-017-0753-x.
Pubmed: 28497432
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.
Pubmed: 29126136
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