Target Information
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 521535 | ClinicalTrials.gov (NCT00046332) A Study Comparing 4 Doses Of GW810781 Versus Placebo In HIV-Infected Patients. U.S. National Institutes of Health. | ||||
Ref 521915 | ClinicalTrials.gov (NCT00398125) Monotherapy Versus Placebo Over 10 Days in Integrase Naive HIV-1 Infected Adults. U.S. National Institutes of Health. | ||||
Ref 525690 | Why have ten or so nontoxic, retrovirus integrase inhibitors not been made available for AIDS treatment. Biomed Pharmacother. 1999 Dec;53(10):484-6. | ||||
Ref 529886 | Preclinical evaluation of GS-9160, a novel inhibitor of human immunodeficiency virus type 1 integrase. Antimicrob Agents Chemother. 2009 Mar;53(3):1194-203. | ||||
Ref 532094 | Repositioning 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 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 548866 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029709) | ||||
Ref 525690 | Why have ten or so nontoxic, retrovirus integrase inhibitors not been made available for AIDS treatment. Biomed Pharmacother. 1999 Dec;53(10):484-6. | ||||
Ref 528782 | Calculation 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 529234 | The 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 529886 | Preclinical evaluation of GS-9160, a novel inhibitor of human immunodeficiency virus type 1 integrase. Antimicrob Agents Chemother. 2009 Mar;53(3):1194-203. | ||||
Ref 529974 | Raltegravir: the first HIV type 1 integrase inhibitor. Clin Infect Dis. 2009 Apr 1;48(7):931-9. | ||||
Ref 530462 | Elvitegravir: a new HIV integrase inhibitor. Antivir Chem Chemother. 2009 Oct 19;20(2):79-85. | ||||
Ref 538078 | Dicaffeoylquinic and dicaffeoyltartaric acids are selective inhibitors of human immunodeficiency virus type 1 integrase. Antimicrob Agents Chemother. 1998 Jan;42(1):140-6. |
If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.