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Pathway Description
Fosamprenavir Action Pathway
Homo sapiens
Drug Action Pathway
Fosamprenavir is an antiretroviral agent and prodrug of amprenavir used for the treatment and postexposure prophylaxis of human immunodeficiency virus (HIV-1) infection. Fosamprenavir is a prodrug that is rapidly hydrolyzed to amprenavir by cellular phosphatases in the gut epithelium as it is absorbed. Amprenavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). It is transported into the blood then to the infected cells where it inhibits HIV-1 protease.
The HIV virus binds and penetrates host cell. Viral RNA is transcribed into viral DNA via reverse transcriptase. Viral DNA enters the host nucleus and is integrated into the host DNA via integrase. The DNA is then transcribed, creating viral mRNA. Viral mRNA is translater into the gag-pol polyprotein. HIV protease is synthesized as part of the Gag-pol polyprotein, where Gag encodes for the capsid and matrix protein to form the outer protein shell, and Pol encodes for the reverse transcriptase and integrase protein to synthesize and incorporate its genome into host cells. HIV-1 protease cleaves the Gag-pol polyprotein into 66 molecular species, including HIV-1 protease, integrase, and reverse transcriptase. Amprenavir inhibits HIV-1 protease. This inhibition prevents the HIV virion from fully maturing and becoming infective. Using the lipid bilayer of the host cell, a virus is formed and released. The inhibition of HIV-1 protease prevents the necessary molecular species from forming, therefore preventing maturation and activation of viral particles. This forms immature, non-infectious viral particles, therefore, Amprenavir prevents the virus from reproducing.
References
Fosamprenavir Pathway References
Konnyu B, Sadiq SK, Turanyi T, Hirmondo R, Muller B, Krausslich HG, Coveney PV, Muller V: Gag-Pol processing during HIV-1 virion maturation: a systems biology approach. PLoS Comput Biol. 2013;9(6):e1003103. doi: 10.1371/journal.pcbi.1003103. Epub 2013 Jun 6.
Pubmed: 23754941
Zephyr J, Kurt Yilmaz N, Schiffer CA: Viral proteases: Structure, mechanism and inhibition. Enzymes. 2021;50:301-333. doi: 10.1016/bs.enz.2021.09.004. Epub 2021 Nov 17.
Pubmed: 34861941
Louten J. Virus Replication. Essential Human Virology. 2016:49–70. doi: 10.1016/B978-0-12-800947-5.00004-1. Epub 2016 May 6. PMCID: PMC7149683.
Wittayanarakul K, Hannongbua S, Feig M: Accurate prediction of protonation state as a prerequisite for reliable MM-PB(GB)SA binding free energy calculations of HIV-1 protease inhibitors. J Comput Chem. 2008 Apr 15;29(5):673-85. doi: 10.1002/jcc.20821.
Pubmed: 17849388
Sadler BM, Hanson CD, Chittick GE, Symonds WT, Roskell NS: Safety and pharmacokinetics of amprenavir (141W94), a human immunodeficiency virus (HIV) type 1 protease inhibitor, following oral administration of single doses to HIV-infected adults. Antimicrob Agents Chemother. 1999 Jul;43(7):1686-92. doi: 10.1128/AAC.43.7.1686.
Pubmed: 10390223
Amprenavir: a new HIV protease inhibitor. Med Lett Drugs Ther. 1999 Jul 16;41(1057):64-6.
Pubmed: 10436772
Smith KY, Weinberg WG, DeJesus E, Fischl MA, Liao Q, Ross LL, Pakes GE, Pappa KA, Lancaster CT: Fosamprenavir or atazanavir once daily boosted with ritonavir 100 mg, plus tenofovir/emtricitabine, for the initial treatment of HIV infection: 48-week results of ALERT. AIDS Res Ther. 2008 Mar 28;5:5. doi: 10.1186/1742-6405-5-5.
Pubmed: 18373851
Furfine ES, Baker CT, Hale MR, Reynolds DJ, Salisbury JA, Searle AD, Studenberg SD, Todd D, Tung RD, Spaltenstein A: Preclinical pharmacology and pharmacokinetics of GW433908, a water-soluble prodrug of the human immunodeficiency virus protease inhibitor amprenavir. Antimicrob Agents Chemother. 2004 Mar;48(3):791-8. doi: 10.1128/AAC.48.3.791-798.2004.
Pubmed: 14982766
Hoffman RM, Umeh OC, Garris C, Givens N, Currier JS: Evaluation of sex differences of fosamprenavir (with and without ritonavir) in HIV-infected men and women. HIV Clin Trials. 2007 Nov-Dec;8(6):371-80. doi: 10.1310/hct0806-371.
Pubmed: 18042502
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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