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WO2010067980A2 - Inhibiteur d'histone déacétylase réactivant le provirus vih-1 dans des cellules infectées par le vih latent - Google Patents

Inhibiteur d'histone déacétylase réactivant le provirus vih-1 dans des cellules infectées par le vih latent Download PDF

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Publication number
WO2010067980A2
WO2010067980A2 PCT/KR2009/007162 KR2009007162W WO2010067980A2 WO 2010067980 A2 WO2010067980 A2 WO 2010067980A2 KR 2009007162 W KR2009007162 W KR 2009007162W WO 2010067980 A2 WO2010067980 A2 WO 2010067980A2
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hiv
methyl
naphthalen
oxy
hydroxy
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PCT/KR2009/007162
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English (en)
Korean (ko)
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WO2010067980A3 (fr
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홍기종
최병선
김성순
이학성
노성구
현영란
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대한민국(관리부서 질병관리본부장)
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Priority to KR1020117012184A priority Critical patent/KR101388596B1/ko
Publication of WO2010067980A2 publication Critical patent/WO2010067980A2/fr
Publication of WO2010067980A3 publication Critical patent/WO2010067980A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present invention relates to HDAC inhibitors capable of efficiently reactivating HIV-1 provirus in latent HIV infected cells and methods of reactivating HIV-1 provirus from latent HIV infected cells using the inhibitor.
  • Histones are the central proteins that make up chromatin, acting as a winding axis of DNA, helping to condense DNA and play an important role in regulating gene expression (Strahl et al , 2000, Nature 403: 41-45; Shahbazian et al , 2007 , Annu Rev Biochem 76: 75-100).
  • histones are susceptible to chromatin modifications that regulate gene expression by acetylation, methylation, and the like, and changes in gene expression are also associated with the latent nature of HIV (Khorasanizadeh, 2004, Cell 116). : 259-272).
  • HIV Human Immunodeficiency Virus
  • AIDS HIV-associated Virus
  • Multidrug therapy such as Highly Active Anti-Retroviral Therapy (HAART)
  • HAART Highly Active Anti-Retroviral Therapy
  • Histone deacetylase inhibits the expression of the HIV-1 gene from memory CD4 + T cells, an HIV-1 latent infectious pathogen (Ylisastigui et al , 2005, Journal of Infectious Diseases, 190: 1429-1437). That is, HDAC binds to the HIV-1 LTR promoter and inhibits HIV-1 virus replication, thereby enabling the production of latent HIV-1 infected cells as HIV-1 reservoirs. Therefore, to effectively remove inactive HIV-1 latent memory T cells from HIV and AIDS patients, HDAC activity must be inhibited.
  • HDACi HDAC inhibitors
  • valproic acid valproic acid
  • SAHA suberoylanilide hydroxamic acid
  • An object of the present invention is to provide an HDAC inhibitor capable of efficiently reactivating HIV-1 provirus in a latent HIV infected cell and a method for reactivating HIV-1 provirus using the same. Accordingly, the HDAC inhibitor can be treated with a cocktail therapy drug of HARRT, including other transcriptase inhibitors, such as AZT, or other AIDS agents, thereby making it possible to efficiently reduce or eliminate latent HIV pathogens. .
  • the present invention relates to a histone deacetylase inhibitor of formula 1 for reactivating HIV-1 provirus from latent HIV infected cells.
  • Each R 1 is independently C 1-3 alkyl, hydroxyC 1-2 alkyl, haloC 1-2 alkyl, piperidinyl, morpholinyl, cyanomethyl, piperazinyl, diC 1-2 alkylamino C 1-2 alkyl, diC 1-2 alkylaminoC 1-2 alkyl, piperidinylC 1-2 alkyl, morpholinoC 1-2 alkyl, piperazinoC 1-2 alkyl, pyrrolidinyl, C and C 1-2 alkyl optionally substituted with one or more substituents selected from the group consisting of 1-2-alkyl-pyrrolidinyl,
  • R 2 is hydrogen or methyl.
  • said latent HIV infected cells are ACH2 cells or J1.1 cells.
  • the latent HIV infected cells are ACH2 cells.
  • the present invention also relates to a method of reactivating HIV-1 provirus from latent HIV infected cells using the histone deacetylase inhibitor.
  • the HDAC inhibitors of the present invention have the ability to reactivate HIV-1 proviruses with low efficacy compared to the high stability of conventional HDAC inhibitors, or have high reactivation ability but at the same time stability and efficacy in treating HIV due to high cytotoxicity Compared with failure to obtain, relatively low cytotoxicity and high HIV-1 proviral reactivation result in more effective reactivation of latent HIV-1 virus from CD4 + T cells, an HIV-1 chronic infectious pathogen. Accordingly, by treating the HDAC inhibitor with the currently used HIV therapeutic agent, reverse transcriptase inhibitor and protease inhibitor, the virus pathogen of the latent HIV-infected cells can be efficiently removed by suppressing the virus released into the extracellular space or cytoplasm. I could do it.
  • FIG. 8 shows HIV-1 p24 antigen production capacity measured after treatment of HDAC inhibitors at a concentration of 0.14 ⁇ M single treatment.
  • FIG. 10 shows cell viability and HIV-1 p24 antigen production capacity in J 1.1 cells for PXD-101.
  • FIG. 11 depicts cell viability and HIV-1 p24 antigen production capacity in J 1.1 cells for CG0005.
  • Figure 12 depicts cell viability and HIV-1 p24 antigen production capacity in J 1.1 cells for CG0006.
  • FIG. 13 shows changes in HIV-1 p24 antigen inside ACH2 cells after HDAC inhibitor treatment.
  • Figure 14 shows the change in expression of CD28, an immune cell activation marker after HDAC inhibitor treatment.
  • FIG. 15 shows the change in expression of signal material (RANTES) related to physiological signal transduction associated with response inside ACH2 cells after HDAC inhibitor treatment.
  • RANTES signal material
  • Figure 16 shows changes in the expression of signaling materials (PD-1 receptor and PD-L1 ligand) involved in the transmission of physiological signals related to responses inside ACH2 cells after HDAC inhibitor treatment.
  • signaling materials PD-1 receptor and PD-L1 ligand
  • FIG. 18 depicts acetylation and methylation in each portion of histone H3 protein, represented by Western Blot after treatment with HDAC inhibitors.
  • Latent HIV-1 infected cell lines J1.1 and ACH2 cells were treated with HDAC inhibitors to reactivate viral replication of HIV-1 pathogens.
  • CG0006 showed low cytotoxicity (CD 50 : 0.1-0.3 ⁇ M) compared to SAHA (CD 50 : 0.3 ⁇ M) or PXD-101 (CD 50 : 0.1-0.3 ⁇ M).
  • MTT assay Roche
  • CG0006 showed low cytotoxicity (CD 50 : 0.1-0.3 ⁇ M) compared to SAHA (CD 50 : 0.3 ⁇ M) or PXD-101 (CD 50 : 0.1-0.3 ⁇ M).
  • the results of cytotoxicity experiments showing the stability of CG0005 and CG0006 in comparison with SAHA, PXD-101 are shown in FIG. 1.
  • the cells were treated with HDAC inhibitors, and then the amount of HIV-1 p24 antigen generated in the cell culture was measured using the Vironostika HIV-1 Antigen MicroELISA Kit (BioMerieux). (HIV-1 Gag p24 antigen ELISA).
  • the J1.1 and ACH2 cell lines treated with CG0005 and CG0006 produced more HIV-1 p24 antigen at lower concentration than the positive control treated with SAHA and PXD-101 as a positive control.
  • ED 50 was about 0.1 ⁇ M for CG0005 and about 0.05 ⁇ M for CG0006.
  • Figure 2 is the result of measuring the amount of HIV-1 p24 antigen discharged to the cell culture in accordance with HIV-1 provirus reactivation by ELISA method.
  • Figures 3 to 6 the cell viability and HIV-1 p24 antigen generation capacity in ACH2 cells for each HDAC inhibitor based on the results of Figures 1 and 2, CD 50 (Cytotoxic dose 50) and ED 50 (Effective) dose 50).
  • CD 50 Cytotoxic dose 50
  • ED 50 Effective dose 50
  • 1 provirus reactivation capacity is shown (FIGS. 5, 6).
  • 7 and 8 are the results of comparing the cytotoxicity and HIV p24 antigen production at a single treatment concentration of 0.14 ⁇ M determined in consideration of the stability and reactivation
  • J1.1 cells, CG0005 and CG0006 were similar to those of the ACH2 cell line.
  • ED 50 was better than SAHA and PXD-101 (0.1 ⁇ M), and the amount of HIV-1 p24 antigen upon reactivation was also superior to PXD-101 or SAHA (FIGS. 9 to 12).
  • the percentage of cells expressing intracellular HIV-1 p24 antigen was measured by flow cytometry. Measured. After treatment with HDAC inhibitor, the cultured cells were pretreated with Perm / Fix reagent (BD Sciences) for 15 minutes, stained with KC57 (p24) -RD1 antibody (Beckman Coulter) for 20 minutes, and then FC500 flow cytometer (FC500 Flow cytometer). , Beckman Coulter) was used to measure the cells. After 24 hours of treatment, the percentage of cells expressing HIV-1 p24 antigen in the cells treated with CG0005 and CG0006 increased rapidly. After 48 hours, the percentage of cells expressing HIV-1 p24 antigen was somewhat higher than that of 24 hours. It was reduced, but remained at a high level compared to the control or cells treated with SAHA and PXD-101 inhibitors.
  • CD28 expression patterns of activation markers on the surface of immune cells were measured by flow cytometry.
  • Cells cultured after drug treatment were stained with CD28-ECD antibody (Beckman Coulter) for 20 minutes without pretreatment, and analyzed using FC500 flow cytometer (FC500 Flow cytometer, Beckman Coulter).
  • FIG. 14 shows the extent to which CD28 expression, an immune cell surface activation marker, is increased by each HDAC inhibitor treatment. Gray sections show CD28 expression in control cells not treated with HDAC inhibitors, and white sections show CD28 expression in cells treated with HDAC inhibitors. CD28 expression was increased after HDAC inhibitor treatment, and CD28 expression was significantly higher in cells treated with CG0005 and CG0006. This trend is consistent up to 48 hours after treatment.
  • test tube 1 was RANTES-PE (BD Sciences)
  • test tube 2 was CD279 ( After staining with a mixture of PD-1) -PE and CD274 (PD-L1) -FITC (BD Sciences), they were analyzed using an FC500 flow cytometer (Beckman Coulter).
  • the intracellular RANTES production tended to increase in PXD-101 and CG0006 treated cells compared to SAHA.
  • the expression of apoptosis markers PD-1 receptor (Programmed Death receptor 1) and PD-L1 ligand (Programmed Death Receptor 1 ligand) in ACH2 cells, HIV-1 chronically infected cell lines, compared to non HIV-1 infected cells The aspect of change and the recovery of this change by HDAC inhibitor treatment were measured.
  • the gray colored peaks indicate intracellular RANTES expression levels in ACH2 cells, which are chronically infected cell lines without drug treatment, and the white areas indicate increased intracellular RANTES expression levels by HDAC inhibitors.
  • CG0005 and CG0006 showed locally increased RANTES expression compared to SAHA.
  • FIG. 16 shows the distribution of PD-1 (the yellow portion at the bottom right of each diagram) and PD-L1 (the red portion at the top left of the diagram), compared to A3.01 cells, which are not infected cells.
  • PD-L1 ligand-expressing cells the relatively high proportion of PD-L1 ligand-expressing cells and half the low PD-1 receptor-expressing cells in chronically infected cell lines, ACH2 cells, these changes caused by chronic infection when treated with HDAC inhibitors were observed.
  • the percentage of receptor expressing cells was higher and the ratio of PD-L1 expressing cells was somewhat lower, i.e. recovery in the opposite direction was shown.
  • the degree of acetylation of histone H3 protein which is known to be involved in HIV-1 provirus reactivation from HIV-1 chronically infected cells, was measured using an ELISA kit from Cell Signaling.
  • NFkB nuclear fator kappa B
  • MSA Panomics' electrophoretic mobility shift assay
  • CG0005 and CG0006 of the present invention compared with other conventional inhibitors, induce the activation of NFkB involved in promoting acetylation of histone H3 protein and increasing transcriptional activity upon HIV reactivation, thereby preventing from latent HIV infected cells. It was confirmed that it has the ability to reactivate HIV-1 provirus.

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Abstract

La présente invention concerne un inhibiteur d'histone déacétylase (HDAC) de formule chimique 1, qui permet la réactivation du provirus VIH-1 à partir de cellules infectées par le VIH latent. L'invention porte en outre sur un procédé de réactivation du provirus VIH-1 à partir de cellules infectées par le VIH latent au moyen dudit inhibiteur. Ledit HDAC présente une faible toxicité cellulaire et une stabilité élevée, de telle sorte qu'il peut réactiver efficacement le provirus VIH-1 latent à partir du réservoir de cellules CD4+ T. En conséquence, ledit inhibiteur HDAC est traité avec une combinaison de médicaments thérapeutiques HAART, tels que l'AZT inhibiteur de la transcriptase inverse, de sorte que le réservoir de VIH latent peut être réduit ou retiré efficacement.
PCT/KR2009/007162 2008-12-11 2009-12-02 Inhibiteur d'histone déacétylase réactivant le provirus vih-1 dans des cellules infectées par le vih latent WO2010067980A2 (fr)

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KR1020117012184A KR101388596B1 (ko) 2008-12-11 2009-12-02 잠복성 hiv 감염 세포에서 hiv-1 프로바이러스를 재활성화시키는 히스톤 디아세틸라제 억제제

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105597090A (zh) * 2014-11-14 2016-05-25 中国科学院上海生命科学研究院 一种提高cd4阳性t淋巴细胞存活率和活性的试剂及其应用
CN110740989A (zh) * 2017-06-15 2020-01-31 晶体基因技术株式会社 烷基氨基甲酰基萘氧基辛烯酰基羟基酰胺的或其衍生物的药学上可接受的盐及其制备方法
US11311603B2 (en) 2018-06-19 2022-04-26 Nantcell, Inc. HIV treatment compositions and methods

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102678356B1 (ko) * 2018-10-29 2024-06-26 씨지인바이츠 주식회사 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 인산염, 타르타르산염 또는 이들의 조합을 포함하는 약제학적 조성물 및 그 제조방법
KR20220118747A (ko) * 2021-02-19 2022-08-26 크리스탈지노믹스(주) 제2형 중증급성호흡기증후군 코로나바이러스 감염증 예방 또는 치료용 약학 조성물

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004076386A2 (fr) * 2003-02-25 2004-09-10 Topotarget Uk Limited Composes d'acide carbamique comprenant un groupe heteroaryle bicyclique utilises en tant qu'inhibiteurs de hdac
WO2007052938A1 (fr) * 2005-11-01 2007-05-10 Korea Research Institute Of Chemical Technology Dérivés d’alkylcarbamoylnaphtalényloxyocténoylhydroxyamide présentant une activité inhibitrice vis-à-vis de l'histone désacétylase et synthèse desdits dérivés
WO2008068170A1 (fr) * 2006-12-04 2008-06-12 William Paul Jackson Inhibiteurs de l'hdac

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004076386A2 (fr) * 2003-02-25 2004-09-10 Topotarget Uk Limited Composes d'acide carbamique comprenant un groupe heteroaryle bicyclique utilises en tant qu'inhibiteurs de hdac
WO2007052938A1 (fr) * 2005-11-01 2007-05-10 Korea Research Institute Of Chemical Technology Dérivés d’alkylcarbamoylnaphtalényloxyocténoylhydroxyamide présentant une activité inhibitrice vis-à-vis de l'histone désacétylase et synthèse desdits dérivés
WO2008068170A1 (fr) * 2006-12-04 2008-06-12 William Paul Jackson Inhibiteurs de l'hdac

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YLISASTIGUI, LOYDA ET AL.: 'Coaxing HIV-1 from resting CD4 T cells: histone deacetylase inhibition allows latent viral expression' AIDS vol. 18, no. ISSUE, 21 May 2004, pages 1101 - 1108 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105597090A (zh) * 2014-11-14 2016-05-25 中国科学院上海生命科学研究院 一种提高cd4阳性t淋巴细胞存活率和活性的试剂及其应用
CN110740989A (zh) * 2017-06-15 2020-01-31 晶体基因技术株式会社 烷基氨基甲酰基萘氧基辛烯酰基羟基酰胺的或其衍生物的药学上可接受的盐及其制备方法
RU2736216C1 (ru) * 2017-06-15 2020-11-12 Кристалдженомикс, Инк. Фармацевтически приемлемая соль алкилкарбамоилнафталенилоксиоктеноилгидроксиамида или его производного и способ ее получения
CN110740989B (zh) * 2017-06-15 2022-03-08 晶体基因技术株式会社 烷基氨基甲酰基萘氧基辛烯酰基羟基酰胺的或其衍生物的药学上可接受的盐及其制备方法
US11655207B2 (en) 2017-06-15 2023-05-23 Crystalgenomics, Inc. Pharmaceutically acceptable salt of alkylcarbamoyl naphthalenyloxy octenoylhydroxy amide or of derivative thereof and method for preparing same
US11311603B2 (en) 2018-06-19 2022-04-26 Nantcell, Inc. HIV treatment compositions and methods
US11786577B2 (en) 2018-06-19 2023-10-17 Nantcell, Inc. HIV treatment compositions and methods

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WO2010067980A3 (fr) 2010-09-23
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