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Pathway Description
Dolutegravir Action Pathway
Homo sapiens
Category:
Metabolite Pathway
Sub-Category:
Drug Action
Created: 2023-03-15
Last Updated: 2023-10-25
Dolutegravir is an HIV-1 integrase inhibitor used for the tratement of HIV-1 in combination with other antiretroviral agents.
Dolutegravir inhibits HIV integrase by binding to the active site and blocking the strand transfer step of retroviral DNA integration in the host cell. The strand transfer step is essential in the HIV replication cycle and results in the inhibition of viral activity. Dolutegravir is transported into the infected cell then transported into the nucleus via importin nuclear transporter.The viral RNA is injected into the cell then transcribed into viral DNA via reverse transcriptase. It is then transported into the nucleus where it is integrated into the host DNA. Raltegravir inhibits HIV integrase which prevents the viral DNA from being integrated into the host DNA. This prevents viral replication and further progression of the virus.
References
Dolutegravir Pathway References
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Pubmed: 19884365
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Pubmed: 21381981
Min S, Sloan L, DeJesus E, Hawkins T, McCurdy L, Song I, Stroder R, Chen S, Underwood M, Fujiwara T, Piscitelli S, Lalezari J: Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults. AIDS. 2011 Sep 10;25(14):1737-45. doi: 10.1097/QAD.0b013e32834a1dd9.
Pubmed: 21716073
Hare S, Smith SJ, Metifiot M, Jaxa-Chamiec A, Pommier Y, Hughes SH, Cherepanov P: Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol Pharmacol. 2011 Oct;80(4):565-72. doi: 10.1124/mol.111.073189. Epub 2011 Jun 30.
Pubmed: 21719464
Katlama C, Murphy R: Dolutegravir for the treatment of HIV. Expert Opin Investig Drugs. 2012 Apr;21(4):523-30. doi: 10.1517/13543784.2012.661713. Epub 2012 Mar 2.
Pubmed: 22380682
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Pubmed: 23830355
Dolutegravir (Tivicay) for HIV. Med Lett Drugs Ther. 2013 Sep 30;55(1426):77-9.
Pubmed: 24081387
Cottrell ML, Hadzic T, Kashuba AD: Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir. Clin Pharmacokinet. 2013 Nov;52(11):981-94. doi: 10.1007/s40262-013-0093-2.
Pubmed: 23824675
Underwood MR, Johns BA, Sato A, Martin JN, Deeks SG, Fujiwara T: The activity of the integrase inhibitor dolutegravir against HIV-1 variants isolated from raltegravir-treated adults. J Acquir Immune Defic Syndr. 2012 Nov 1;61(3):297-301. doi: 10.1097/QAI.0b013e31826bfd02.
Pubmed: 22878423
Rathbun RC, Lockhart SM, Miller MM, Liedtke MD: Dolutegravir, a second-generation integrase inhibitor for the treatment of HIV-1 infection. Ann Pharmacother. 2014 Mar;48(3):395-403. doi: 10.1177/1060028013513558. Epub 2013 Nov 19.
Pubmed: 24259658
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Pubmed: 29126136
Tseng SF, Chang CY, Wu KJ, Teng SC: Importin KPNA2 is required for proper nuclear localization and multiple functions of NBS1. J Biol Chem. 2005 Nov 25;280(47):39594-600. doi: 10.1074/jbc.M508425200. Epub 2005 Sep 27.
Pubmed: 16188882
Weis K, Mattaj IW, Lamond AI: Identification of hSRP1 alpha as a functional receptor for nuclear localization sequences. Science. 1995 May 19;268(5213):1049-53. doi: 10.1126/science.7754385.
Pubmed: 7754385
Dorr SN, Schlicker MN, Hansmann IN: Genomic structure of karyopherin alpha2 ( KPNA2) within a low-copy repeat on chromosome 17q23-q24 and mutation analysis in patients with Russell-Silver syndrome. Hum Genet. 2001 Nov;109(5):479-86. doi: 10.1007/s004390100605. Epub 2001 Oct 3.
Pubmed: 11735022
Chi NC, Adam EJ, Adam SA: Sequence and characterization of cytoplasmic nuclear protein import factor p97. J Cell Biol. 1995 Jul;130(2):265-74. doi: 10.1083/jcb.130.2.265.
Pubmed: 7615630
Gorlich D, Kostka S, Kraft R, Dingwall C, Laskey RA, Hartmann E, Prehn S: Two different subunits of importin cooperate to recognize nuclear localization signals and bind them to the nuclear envelope. Curr Biol. 1995 Apr 1;5(4):383-92. doi: 10.1016/s0960-9822(95)00079-0.
Pubmed: 7627554
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Pubmed: 14702039
Srimaroeng C, Chatsudthipong V, Aslamkhan AG, Pritchard JB: Transport of the natural sweetener stevioside and its aglycone steviol by human organic anion transporter (hOAT1; SLC22A6) and hOAT3 (SLC22A8). J Pharmacol Exp Ther. 2005 May;313(2):621-8. doi: 10.1124/jpet.104.080366. Epub 2005 Jan 11.
Pubmed: 15644426
Mizuno N, Takahashi T, Iwase Y, Kusuhara H, Niwa T, Sugiyama Y: Human organic anion transporters 1 (hOAT1/SLC22A6) and 3 (hOAT3/SLC22A8) transport edaravone (MCI-186; 3-methyl-1-phenyl-2-pyrazolin-5-one) and its sulfate conjugate. Drug Metab Dispos. 2007 Aug;35(8):1429-34. doi: 10.1124/dmd.106.013912. Epub 2007 May 14.
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Pubmed: 15914676
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