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Pathway Description
Lopinavir Action Pathway
Homo sapiens
Category:
Metabolite Pathway
Sub-Category:
Drug Action
Created: 2023-03-23
Last Updated: 2023-10-25
Lopinavir is an antiretroviral HIV-1 protease inhibitor used in combination with ritonavir to treat human immunodeficiency virus (HIV) infection. Lopinavir is marketed and administered exclusively in combination with ritonavir. This combination is necessary due to lopinavir's poor oral bioavailability and extensive biotransformation.
The HIV virus binds and penetrates the 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. Lopinavir 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, Lopinavir prevents the virus from reproducing.
References
Lopinavir 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.
Li F, Lu J, Ma X: CYP3A4-mediated lopinavir bioactivation and its inhibition by ritonavir. Drug Metab Dispos. 2012 Jan;40(1):18-24. doi: 10.1124/dmd.111.041400. Epub 2011 Sep 27.
Pubmed: 21953914
Sundquist WI, Krausslich HG: HIV-1 assembly, budding, and maturation. Cold Spring Harb Perspect Med. 2012 Jul;2(7):a006924. doi: 10.1101/cshperspect.a006924.
Pubmed: 22762019
Sham HL, Kempf DJ, Molla A, Marsh KC, Kumar GN, Chen CM, Kati W, Stewart K, Lal R, Hsu A, Betebenner D, Korneyeva M, Vasavanonda S, McDonald E, Saldivar A, Wideburg N, Chen X, Niu P, Park C, Jayanti V, Grabowski B, Granneman GR, Sun E, Japour AJ, Leonard JM, Plattner JJ, Norbeck DW: ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob Agents Chemother. 1998 Dec;42(12):3218-24. doi: 10.1128/AAC.42.12.3218.
Pubmed: 9835517
Kumar GN, Jayanti V, Lee RD, Whittern DN, Uchic J, Thomas S, Johnson P, Grabowski B, Sham H, Betebenner D, Kempf DJ, Denissen JF: In vitro metabolism of the HIV-1 protease inhibitor ABT-378: species comparison and metabolite identification. Drug Metab Dispos. 1999 Jan;27(1):86-91.
Pubmed: 9884314
Garriga C, Perez-Elias MJ, Delgado R, Ruiz L, Najera R, Pumarola T, Alonso-Socas Mdel M, Garcia-Bujalance S, Menendez-Arias L: Mutational patterns and correlated amino acid substitutions in the HIV-1 protease after virological failure to nelfinavir- and lopinavir/ritonavir-based treatments. J Med Virol. 2007 Nov;79(11):1617-28. doi: 10.1002/jmv.20986.
Pubmed: 17854027
Lopinavir/ritonavir: a protease inhibitor combination. Med Lett Drugs Ther. 2001 Jan 8;43(1095):1-2.
Pubmed: 11151088
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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