Target Information
| Target General Information | Top | |||||
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| Target ID |
T39087
(Former ID: TTDC00211)
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| Target Name |
Human immunodeficiency virus Integrase (HIV IN)
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| Synonyms |
HIV IN
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| Gene Name |
HIV IN
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Human immunodeficiency virus disease [ICD-11: 1C60-1C62] | |||||
| Function |
Gag-Pol polyprotein: Mediates, with Gag polyprotein, the essential events in virion assembly, including binding the plasma membrane, making the protein-protein interactions necessary to create spherical particles, recruiting the viral Env proteins, and packaging the genomic RNA via direct interactions with the RNA packaging sequence (Psi). Gag-Pol polyprotein may regulate its own translation, by the binding genomic RNA in the 5'-UTR. At low concentration, the polyprotein would promote translation, whereas at high concentration, the polyprotein would encapsidate genomic RNA and then shut off translation.
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| BioChemical Class |
Integrase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.7.-
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| Sequence |
FLDGIDKAQDEHEKYHSNWRAMASDFNLPPVVAKEIVASCDKCQLKGEAMHGQVDCSPGI
WQLDCTHLEGKVILVAVHVASGYIEAEVIPAETGQETAYFLLKLAGRWPVKTIHTDNGSN FTSATVKAACWWAGIKQEFGIPYNPQSQGVVESMNKELKKIIGQVRDQAEHLKTAVQMAV FIHNFKRKGGIGGYSAGERIVDIIATDIQTKELQKQITKIQNFRVYYRDSRNPLWKGPAK LLWKGEGAVVIQDNSDIKVVPRRKAKIIRDYGKQMAGDDCVASRQDED Click to Show/Hide
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| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 4 Approved Drugs | + | ||||
| 1 | Bictegravir, emtricitabine and tenofovir alafenamide | Drug Info | Approved | Human immunodeficiency virus infection | [2] | |
| 2 | Dolutegravir | Drug Info | Approved | Human immunodeficiency virus infection | [1], [3] | |
| 3 | Elvitegravir | Drug Info | Approved | Human immunodeficiency virus infection | [1] | |
| 4 | Raltegravir | Drug Info | Approved | Human immunodeficiency virus infection | [4] | |
| Clinical Trial Drug(s) | [+] 7 Clinical Trial Drugs | + | ||||
| 1 | GSK1265744 | Drug Info | Phase 3 | Human immunodeficiency virus infection | [5] | |
| 2 | S-1360 | Drug Info | Phase 2 | Human immunodeficiency virus infection | [6] | |
| 3 | S-364735 | Drug Info | Phase 2 | Human immunodeficiency virus infection | [7] | |
| 4 | Acriflavine | Drug Info | Phase 1 | Human immunodeficiency virus infection | [8] | |
| 5 | C-2507 | Drug Info | Phase 1 | Human immunodeficiency virus infection | [9] | |
| 6 | S-265744 LAP | Drug Info | Phase 1 | Human immunodeficiency virus infection | [10] | |
| 7 | VH4524184 | Drug Info | Phase 1 | Human immunodeficiency virus infection | [11] | |
| Discontinued Drug(s) | [+] 3 Discontinued Drugs | + | ||||
| 1 | JTK-656 | Drug Info | Discontinued in Phase 1 | Human immunodeficiency virus infection | [12] | |
| 2 | AR177 | Drug Info | Terminated | Human immunodeficiency virus infection | [13] | |
| 3 | GS-9160 | Drug Info | Terminated | Human immunodeficiency virus infection | [14] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 17 Inhibitor drugs | + | ||||
| 1 | Bictegravir, emtricitabine and tenofovir alafenamide | Drug Info | [2] | |||
| 2 | GSK1265744 | Drug Info | [15] | |||
| 3 | S-1360 | Drug Info | [16], [17] | |||
| 4 | S-364735 | Drug Info | [18] | |||
| 5 | C-2507 | Drug Info | [19] | |||
| 6 | S-265744 LAP | Drug Info | [10], [20] | |||
| 7 | VH4524184 | Drug Info | [21] | |||
| 8 | JTK-656 | Drug Info | [22] | |||
| 9 | AR177 | Drug Info | [23] | |||
| 10 | GS-9160 | Drug Info | [14] | |||
| 11 | Dicaffeoylquinic acids | Drug Info | [24] | |||
| 12 | Dicaffeoyltartaric acids | Drug Info | [24] | |||
| 13 | L-708,906 | Drug Info | [23] | |||
| 14 | L-731,988 | Drug Info | [23] | |||
| 15 | L17 | Drug Info | [23] | |||
| 16 | Purpurin | Drug Info | [25] | |||
| 17 | V-165 | Drug Info | [26] | |||
| Modulator | [+] 4 Modulator drugs | + | ||||
| 1 | Dolutegravir | Drug Info | [1], [10] | |||
| 2 | Elvitegravir | Drug Info | [1] | |||
| 3 | Raltegravir | Drug Info | [4] | |||
| 4 | Acriflavine | Drug Info | [8] | |||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: S-(Dimethylarsenic)Cysteine | Ligand Info | |||||
| Structure Description | Dissociation of biochemical and antiretroviral activities of Integrase-LEDGF Allosteric Inhibitors revealed by resistance of A125 polymorphic HIV-1 | PDB:5OI2 | ||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | No | [27] |
| PDB Sequence |
SPGIWQLDTH
67 LEGKVILVAV77 HVASGYIEAE87 VIPAETGQET97 AYFLLKLAGR107 WPVKTVHTDN 117 GSNFTSTTVK127 AAWWAGIKQM154 NKELKKIIGQ164 VRDQAEHLKT174 AVQMAVFIHN 184 KKRKYSAGER199 IVDIIATDI
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LEU63
4.170
ASP64
1.322
THR66
1.333
HIS67
4.602
VAL72
3.731
ILE73
3.228
LEU74
4.018
VAL75
4.943
ILE89
4.509
GLU92
3.240
THR93
4.556
THR97
3.581
LEU101
3.814
VAL113
3.833
THR115
4.834
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: (2S)-2-tert-butoxy-2-[4-(4,4-dimethylcyclohexen-1-yl)-2-methyl-5-(4-pyridyl)-3-thienyl]acetic acid | Ligand Info | |||||
| Structure Description | Dissociation of biochemical and antiretroviral activities of Integrase-LEDGF Allosteric Inhibitors revealed by resistance of A125 polymorphic HIV-1 | PDB:5OI2 | ||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | No | [27] |
| PDB Sequence |
SPGIWQLDTH
67 LEGKVILVAV77 HVASGYIEAE87 VIPAETGQET97 AYFLLKLAGR107 WPVKTVHTDN 117 GSNFTSTTVK127 AAWWAGIKQM154 NKELKKIIGQ164 VRDQAEHLKT174 AVQMAVFIHN 184 KKRKYSAGER199 IVDIIATDI
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
|---|---|---|---|---|---|---|
| Co-Targets | ||||||
| Target Profiles in Patients | Top | |||||
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| Drug Resistance Mutation (DRM) | ||||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651. | |||||
| REF 2 | 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89. | |||||
| REF 3 | URL: 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 4 | 2007 FDA drug approvals: a year of flux. Nat Rev Drug Discov. 2008 Feb;7(2):107-9. | |||||
| REF 5 | ClinicalTrials.gov (NCT02951052) Study Evaluating the Efficacy, Safety, and Tolerability of Switching to Long-acting Cabotegravir Plus Long-acting Rilpivirine From Current Antiretroviral Regimen in Virologically Suppressed HIV-1-infected Adults. U.S. National Institutes of Health. | |||||
| REF 6 | ClinicalTrials.gov (NCT00046332) A Study Comparing 4 Doses Of GW810781 Versus Placebo In HIV-Infected Patients. U.S. National Institutes of Health. | |||||
| REF 7 | ClinicalTrials.gov (NCT00398125) Monotherapy Versus Placebo Over 10 Days in Integrase Naive HIV-1 Infected Adults. U.S. National Institutes of Health. | |||||
| REF 8 | 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 9 | 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 10 | Clinical pipeline report, company report or official report of Shionogi (2011). | |||||
| REF 11 | ClinicalTrials.gov (NCT05631704) A Phase 1 Double-Blind (Sponsor-unblinded), Placebo-Controlled Randomized, Single and Multiple Ascending Dose First-Time-in-Human Study to Investigate the Safety, Tolerability, and Pharmacokinetics of VH4524184 and the Potential for Changes in Cytochrome P450 3A (CYP3A) Activity. U.S.National Institutes of Health. | |||||
| REF 12 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800030601) | |||||
| REF 13 | Anti-HIV-1 agent AR-177 blocks HIV integrase. AIDS Patient Care STDS. 1996 Feb;10(1):48-9. | |||||
| REF 14 | 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 15 | Clinical pipeline report, company report or official report of GlaxoSmithKline (2009). | |||||
| REF 16 | HIV-1 integrase inhibitors: an emerging clinical reality. Drugs R D. 2007;8(3):155-68. | |||||
| REF 17 | 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. | |||||
| REF 18 | 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. | |||||
| REF 19 | Elvitegravir: a new HIV integrase inhibitor. Antivir Chem Chemother. 2009 Oct 19;20(2):79-85. | |||||
| REF 20 | Long-acting shot prevents infection with HIV analogue. Nature. doi:10.1038/nature.2014.14819. 04 March 2014 | |||||
| REF 21 | Clinical pipeline report, company report or official report of ViiV Healthcare | |||||
| REF 22 | US patent application no. 8,497,270, Macrocyclic integrase inhibitors. | |||||
| REF 23 | Specific inhibition of human immunodeficiency virus type 1 (HIV-1) integration in cell culture: putative inhibitors of HIV-1 integrase. Antimicrob Agents Chemother. 2001 Sep;45(9):2510-6. | |||||
| REF 24 | Dicaffeoylquinic and dicaffeoyltartaric acids are selective inhibitors of human immunodeficiency virus type 1 integrase. Antimicrob Agents Chemother. 1998 Jan;42(1):140-6. | |||||
| REF 25 | Identification of HIV-1 integrase inhibitors based on a four-point pharmacophore. Antivir Chem Chemother. 1998 Nov;9(6):461-72. | |||||
| REF 26 | New class of HIV integrase inhibitors that block viral replication in cell culture. Curr Biol. 2002 Jul 23;12(14):1169-77. | |||||
| REF 27 | Structure-function analyses unravel distinct effects of allosteric inhibitors of HIV-1 integrase on viral maturation and integration. J Biol Chem. 2018 Apr 20;293(16):6172-6186. | |||||
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