Target General Infomation
Target ID
T39087
Former ID
TTDC00211
Target Name
HIV integrase
Gene Name
gag-pol
Synonyms
gag-pol
Target Type
Successful
Disease Human immunodeficiency virus infection [ICD9: 279.3; ICD10: B20-B26]
Function
Integrase: Catalyzes viral DNA integration into the host chromosome, by performing a series of DNA cutting and joining reactions. This enzyme activity takes place after virion entry into a cell and reverse transcription of the RNA genome in dsDNA. The first step in the integration process is 3' processing. This step requires a complex comprising the viral genome, matrix protein, Vpr and integrase. This complex is called the pre- integration complex (PIC). The integrase protein removes 2 nucleotides from each 3' end of the viral DNA, leaving recessed CA OH's at the 3'ends. In the second step, the PIC enters cell nucleus. This process is mediated through integrase and Vpr proteins, and allows the virus to infect a non dividing cell. This ability to enter the nucleus is specific of lentiviruses, other retroviruses cannot and rely on cell division to access cell chromosomes. In the third step, termed strand transfer, the integrase protein joins the previously processed 3' ends to the 5' ends of strands of target cellular DNA at the site of integration. The 5'-ends are produced by integrase-catalyzed staggered cuts, 5 bp apart. A Y-shaped, gapped, recombination intermediate results, with the 5'-ends of the viral DNA strands and the 3' ends of target DNA strands remaining unjoined, flanking a gap of 5 bp. The last step is viral DNA integration into host chromosome. This involves host DNA repair synthesis in which the 5 bp gaps between the unjoined strands are filled in and then ligated. Since this process occurs at both cuts flanking the HIV genome, a 5 bp duplication of host DNA is produced at the ends of HIV-1 integration. Alternatively, Integrase may catalyze the excision of viral DNA just after strand transfer, this is termed disintegration.
BioChemical Class
Integrase
Target Validation
T39087
UniProt ID
EC Number
EC 2.7.7.-
Sequence
FLDGIDKAQDEHEKYHSNWRAMASDFNLPPVVAKEIVASCDKCQLKGEAMHGQVDCSPGI
WQLDCTHLEGKVILVAVHVASGYIEAEVIPAETGQETAYFLLKLAGRWPVKTIHTDNGSN
FTSATVKAACWWAGIKQEFGIPYNPQSQGVVESMNKELKKIIGQVRDQAEHLKTAVQMAV
FIHNFKRKGGIGGYSAGERIVDIIATDIQTKELQKQITKIQNFRVYYRDSRNPLWKGPAK
LLWKGEGAVVIQDNSDIKVVPRRKAKIIRDYGKQMAGDDCVASRQDED
Drugs and Mode of Action
Drug(s) Dolutegravir Drug Info Approved Human immunodeficiency virus infection [532651], [542387]
Elvitegravir Drug Info Approved Human immunodeficiency virus infection [532651]
Raltegravir Drug Info Approved Human immunodeficiency virus infection [529282]
Reformulated raltegravir Drug Info Phase 3 Human immunodeficiency virus infection [551146]
S-349572 Drug Info Phase 3 Human immunodeficiency virus infection [551686]
GSK1265744 Drug Info Phase 2 Human immunodeficiency virus infection [548866]
S-1360 Drug Info Phase 2 Human immunodeficiency virus infection [521535]
S-364735 Drug Info Phase 2 Human immunodeficiency virus infection [521915]
Acriflavine Drug Info Phase 1 Human immunodeficiency virus infection [525690]
C-2507 Drug Info Phase 1 Human immunodeficiency virus infection [532094]
S-265744 LAP Drug Info Phase 1 Human immunodeficiency virus infection [551686]
JTK-656 Drug Info Discontinued in Phase 1 Human immunodeficiency virus infection [548941]
GS-9160 Drug Info Terminated Human immunodeficiency virus infection [529886]
Modulator Acriflavine Drug Info [525690]
Dolutegravir Drug Info [532651]
Elvitegravir Drug Info [532651]
Raltegravir Drug Info [529282]
Reformulated raltegravir Drug Info [529974]
Inhibitor C-2507 Drug Info [530462]
Dicaffeoylquinic acids Drug Info [538078]
Dicaffeoyltartaric acids Drug Info [538078]
GS-9160 Drug Info [529886]
GSK1265744 Drug Info [550963]
JTK-656 Drug Info [550928]
S-1360 Drug Info [528782], [528810]
S-265744 LAP Drug Info [551184], [551686]
S-349572 Drug Info [532651], [551686]
S-364735 Drug Info [529234]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
DRM DRM Info
References
Ref 521535ClinicalTrials.gov (NCT00046332) A Study Comparing 4 Doses Of GW810781 Versus Placebo In HIV-Infected Patients. U.S. National Institutes of Health.
Ref 521915ClinicalTrials.gov (NCT00398125) Monotherapy Versus Placebo Over 10 Days in Integrase Naive HIV-1 Infected Adults. U.S. National Institutes of Health.
Ref 525690Why have ten or so nontoxic, retrovirus integrase inhibitors not been made available for AIDS treatment. Biomed Pharmacother. 1999 Dec;53(10):484-6.
Ref 5292822007 FDA drug approvals: a year of flux. Nat Rev Drug Discov. 2008 Feb;7(2):107-9.
Ref 529886Preclinical evaluation of GS-9160, a novel inhibitor of human immunodeficiency virus type 1 integrase. Antimicrob Agents Chemother. 2009 Mar;53(3):1194-203.
Ref 532094Repositioning HIV-1 integrase inhibitors for cancer therapeutics: 1,6-naphthyridine-7-carboxamide as a promising scaffold with drug-like properties. J Med Chem. 2012 Nov 26;55(22):9492-509.
Ref 5326512013 FDA drug approvals. Nat Rev Drug Discov. 2014 Feb;13(2):85-9.
Ref 542387(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7365).
Ref 548866Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029709)
Ref 548941Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800030601)
Ref 551146Clinical pipeline report, company report or official report of Merck.
Ref 551686Clinical pipeline report, company report or official report of Shionogi (2011).
Ref 525690Why have ten or so nontoxic, retrovirus integrase inhibitors not been made available for AIDS treatment. Biomed Pharmacother. 1999 Dec;53(10):484-6.
Ref 528782Calculation of binding energy using BLYP/MM for the HIV-1 integrase complexed with the S-1360 and two analogues. Bioorg Med Chem. 2007 Jun 1;15(11):3818-24. Epub 2007 Mar 13.
Ref 528810HIV-1 integrase inhibitors: an emerging clinical reality. Drugs R D. 2007;8(3):155-68.
Ref 529234The naphthyridinone GSK364735 is a novel, potent human immunodeficiency virus type 1 integrase inhibitor and antiretroviral. Antimicrob Agents Chemother. 2008 Mar;52(3):901-8. Epub 2007 Dec 26.
Ref 5292822007 FDA drug approvals: a year of flux. Nat Rev Drug Discov. 2008 Feb;7(2):107-9.
Ref 529886Preclinical evaluation of GS-9160, a novel inhibitor of human immunodeficiency virus type 1 integrase. Antimicrob Agents Chemother. 2009 Mar;53(3):1194-203.
Ref 529974Raltegravir: the first HIV type 1 integrase inhibitor. Clin Infect Dis. 2009 Apr 1;48(7):931-9.
Ref 530462Elvitegravir: a new HIV integrase inhibitor. Antivir Chem Chemother. 2009 Oct 19;20(2):79-85.
Ref 5326512013 FDA drug approvals. Nat Rev Drug Discov. 2014 Feb;13(2):85-9.
Ref 538078Dicaffeoylquinic and dicaffeoyltartaric acids are selective inhibitors of human immunodeficiency virus type 1 integrase. Antimicrob Agents Chemother. 1998 Jan;42(1):140-6.
Ref 550928US patent application no. 8,497,270, Macrocyclic integrase inhibitors.
Ref 550963Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
Ref 551184Long-acting shot prevents infection with HIV analogue. Nature. doi:10.1038/nature.2014.14819. 04 March 2014
Ref 551686Clinical pipeline report, company report or official report of Shionogi (2011).

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