Target Information
Target General Information | Top | |||||
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Target ID |
T23343
(Former ID: TTDI02212)
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Target Name |
Human immunodeficiency virus Capsid p24 (HIV p24)
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Synonyms |
CA
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Gene Name |
HIV p24
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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 |
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 processis 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.
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UniProt ID | ||||||
Sequence |
PIVQNIQGQMVHQAISPRTLNAWVKVVEEKAFSPEVIPMFSALSEGATPQDLNTMLNTVG
GHQAAMQMLKETINEEAAEWDRVHPVHAGPIAPGQMREPRGSDIAGTTSTLQEQIGWMTN NPPIPVGEIYKRWIILGLNKIVRMYSPTSILDIRQGPKEPFRDYVDRFYKTLRAEQASQE VKNWMTETLLVQNANPDCKTILKALGPAATLEEMMTACQGVGGPGHKARVL Click to Show/Hide
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Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
1 | Lenacapavir | Drug Info | Approved | Human immunodeficiency virus-1 infection | [2] | |
Clinical Trial Drug(s) | [+] 4 Clinical Trial Drugs | + | ||||
1 | F4co vaccine | Drug Info | Phase 2 | Human immunodeficiency virus infection | [3], [4] | |
2 | Vacc-4x | Drug Info | Phase 2 | Human immunodeficiency virus-1 infection | [5] | |
3 | VH4004280 | Drug Info | Phase 1 | Human immunodeficiency virus infection | [6] | |
4 | VH4011499 | Drug Info | Phase 1 | Human immunodeficiency virus infection | [7] | |
Mode of Action | [+] 1 Modes of Action | + | ||||
Inhibitor | [+] 3 Inhibitor drugs | + | ||||
1 | Lenacapavir | Drug Info | [8] | |||
2 | VH4004280 | Drug Info | [10] | |||
3 | VH4011499 | Drug Info | [10] |
Drug Binding Sites of Target | Top | |||||
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Ligand Name: N-[(1S)-1-[3-[4-chloro-3-(methanesulfonamido)-1-methylindazol-7-yl]-4-oxoquinazolin-2-yl]-2-(3,5-difluorophenyl)ethyl]-2-[3-(difluoromethyl)-2H-cyclopenta[c]pyrazol-1-yl]acetamide | Ligand Info | |||||
Structure Description | Disulfide stabilized HIV-1 CA hexamer in complex with capsid inhibitor N-(1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetamide | PDB:7SNN | ||||
Method | X-ray diffraction | Resolution | 2.37 Å | Mutation | Yes | [11] |
PDB Sequence |
PIVQNLQGQM
10 VHQCISPRTL20 NAWVKVVEEK30 AFSPEVIPMF40 SALSCGATPQ50 DLNTMLNTVG 60 GHQAAMQMLK70 ETINEEAAEW80 DRLHPVHAGP90 IAPGQMREPR100 GSDIAGTTST 110 LQEQIGWMTH120 NPPIPVGEIY130 KRWIILGLNK140 IVRMYSPTSI150 LDIRQGPKEP 160 FRDYVDRFYK170 TLRAEQETLL190 VQNANPDCKT200 ILKALGPGAT210 LEEMMTACQG 220
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Ligand Name: N-[(1S)-1-(3-{4-chloro-3-[(methanesulfonyl)amino]-1-methyl-1H-indazol-7-yl}-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl]-2-[3-(trifluoromethyl)-6,7-dihydro-1H-indazol-1-yl]acetamide | Ligand Info | |||||
Structure Description | Disulfide stabilized HIV-1 CA hexamer in complex with capsid inhibitor N-(1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide | PDB:7SNL | ||||
Method | X-ray diffraction | Resolution | 2.39 Å | Mutation | Yes | [12] |
PDB Sequence |
PIVQNLQGQM
10 VHQCISPRTL20 NAWVKVVEEK30 AFSPEVIPMF40 SALSCGATPQ50 DLNTMLNTVG 60 GHQAAMQMLK70 ETINEEAAEW80 DRLHPVHAGP90 IAPGQMREPR100 GSDIAGTTST 110 LQEQIGWMTH120 NPPIPVGEIY130 KRWIILGLNK140 IVRMYSPTSI150 LDIRQGPKEP 160 FRDYVDRFYK170 TLRAEQETLL190 VQNANPDCKT200 ILKALGPGAT210 LEEMMTACQG 220
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Click to View More Binding Site Information of This Target with Different Ligands |
References | Top | |||||
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REF 1 | EP patent application no. 2621528, Vaccine. | |||||
REF 2 | FDA Approved Drug Products from FDA Official Website. 2022. Application Number: 215973. | |||||
REF 3 | ClinicalTrials.gov (NCT01218113) Efficacy and Safety of GSK Biologicals HIV Vaccine in Antiretroviral Therapy (ART)-naive HIV-1 Infected Persons. U.S. National Institutes of Health. | |||||
REF 4 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027409) | |||||
REF 5 | ClinicalTrials.gov (NCT01712256) Re-boosting of HIV-1 Infected Subjects With Vacc-4x. U.S. National Institutes of Health. | |||||
REF 6 | ClinicalTrials.gov (NCT05163522) A Randomized, Double-Blind (Sponsor Unblinded), Placebo-Controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Orally Administered VH4004280 in Healthy Participants. U.S.National Institutes of Health. | |||||
REF 7 | ClinicalTrials.gov (NCT05393271) A Randomized, Double-Blind (Sponsor Unblinded), Placebo-Controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Orally Administered VH4011499 in Healthy Participants. U.S.National Institutes of Health. | |||||
REF 8 | Clinical pipeline report, company report or official report of Gilead Sciences. | |||||
REF 9 | Clinical pipeline report, company report or official report of Bionor Pharma. | |||||
REF 10 | Clinical pipeline report, company report or official report of ViiV Healthcare | |||||
REF 11 | Disulfide stabilized HIV-1 CA hexamer in complex with capsid inhibitor N-(1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,6-dihydrocyclopenta[c]pyrazol-1(4H)-yl)acetamide | |||||
REF 12 | Disulfide stabilized HIV-1 CA hexamer in complex with capsid inhibitor N-(1-(3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide |
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