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Pathway Description
Sofosbuvir Action Pathway
Homo sapiens
Drug Action Pathway
Sofosbuvir is a direct-acting antiviral agent used to treat specific hepatitis C virus in combination with other anti-viral drugs
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. The genome polyprotein is cleaved by host and viral proteases into 10 viral proteins. The nucleocapsid protein core and the two envelope proteins E1 and E2 form the N terminus of the polyprotein and are the structural components of HCV virions. The precursor also gives rise to the viroporin p7 and six non-structural (NS) proteins. Sofosbuvir is an inhibitor of the Hepatitis C Virus (HCV) Nonstructural protein 5B, which is an RNA-dependent RNA polymerase. RNA polymerase is required for viral RNA replication and assembly of HCV virions. By binding to nonstructural protein 5B outside of the active site of the enzyme, dasabuvir induces a conformational change. Viral RNA replication complexes localize to lipid raft-containing, detergent-resistant membranes created by the viral protein NS4B. For full viral replication and maturation, nonstructural protein 5B is required so viral RNA replication cannot occur. Envelope glycoproteins are acquired through budding into the endoplasmic reticulum lumen. The immature, non-infective virions are released via the cellular golgi apparatus.
References
Sofosbuvir 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
Gentile I, Buonomo AR, Borgia G: Dasabuvir: A Non-Nucleoside Inhibitor of NS5B for the Treatment of Hepatitis C Virus Infection. Rev Recent Clin Trials. 2014;9(2):115-23. doi: 10.2174/1574887109666140529222602.
Pubmed: 24882169
Asselah T: Sofosbuvir for the treatment of hepatitis C virus. Expert Opin Pharmacother. 2014 Jan;15(1):121-30. doi: 10.1517/14656566.2014.857656. Epub 2013 Nov 30.
Pubmed: 24289735
Molina JM, Orkin C, Iser DM, Zamora FX, Nelson M, Stephan C, Massetto B, Gaggar A, Ni L, Svarovskaia E, Brainard D, Subramanian GM, McHutchison JG, Puoti M, Rockstroh JK: Sofosbuvir plus ribavirin for treatment of hepatitis C virus in patients co-infected with HIV (PHOTON-2): a multicentre, open-label, non-randomised, phase 3 study. Lancet. 2015 Mar 21;385(9973):1098-106. doi: 10.1016/S0140-6736(14)62483-1. Epub 2015 Feb 4.
Pubmed: 25659285
Murakami E, Tolstykh T, Bao H, Niu C, Steuer HM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM, Otto MJ, Sofia MJ, Furman PA: Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J Biol Chem. 2010 Nov 5;285(45):34337-47. doi: 10.1074/jbc.M110.161802. Epub 2010 Aug 26.
Pubmed: 20801890
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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