WO2018190680A1 - NUTLINE-3α PERMETTANT DE MAÎTRISER MYCOBACTERIUM TUBERCULOSIS INTRACELLULAIRE, ET COMPOSITION ET MÉTHODE PERMETTANT DE RÉGULER L'EXPRESSION DE P53 - Google Patents
NUTLINE-3α PERMETTANT DE MAÎTRISER MYCOBACTERIUM TUBERCULOSIS INTRACELLULAIRE, ET COMPOSITION ET MÉTHODE PERMETTANT DE RÉGULER L'EXPRESSION DE P53 Download PDFInfo
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- WO2018190680A1 WO2018190680A1 PCT/KR2018/004350 KR2018004350W WO2018190680A1 WO 2018190680 A1 WO2018190680 A1 WO 2018190680A1 KR 2018004350 W KR2018004350 W KR 2018004350W WO 2018190680 A1 WO2018190680 A1 WO 2018190680A1
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- tuberculosis
- nutlin
- mycobacterium tuberculosis
- mycobacterium
- pharmaceutical composition
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Classifications
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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
- A61K31/13—Amines
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
Definitions
- the present invention relates generally to the field of immunology and, in part, to methods of inhibiting survival and proliferation of Mycobacterium tuberculosis and to methods for providing Nutlin-3 ⁇ (neutrin-3 ⁇ ) and p53 expression control compositions.
- Tuberculosis is a chronic infectious disease caused by infection of Mycobacterium tuberculosis and other Mycobacterium species. Tuberculosis is a major disease in developing countries that kills about 8 million new infections each year, killing 3 million lives, and is also a problem in developed countries. While the infection may be asymptomatic for a significant period of time, tuberculosis is the most common symptom, indicating acute inflammation of the lung, resulting in fever and nonproductive cough. If left untreated, it usually results in serious complications and death.
- Tuberculosis can be treated using prolonged antibiotic therapy, but this treatment is not sufficient to prevent the spread of tuberculosis. Infected individuals do not exhibit symptoms but may be contagious for a period of time. In addition, it is difficult to control the patient's behavior even if the treatment regimen is strictly followed. Some patients do not complete the course of treatment, which can lead to ineffective treatment and development of drug resistance. Even when the entire course of treatment is completed, the TB germ infection is not eradicated from the infected individual and remains a latent infection that can still be reactivated.
- BCG Bacillus Calmette-Guerin
- PPD tuberculin proteinpurified derivative
- Antigen-specific T cell responses result in measurable degree induration at the site of infusion up to 48-72 hours post infusion, indicating exposure to mycobacterium antigens.
- the assay is problematic in sensitivity and specificity, and individuals vaccinated with BCG cannot be distinguished from those infected.
- p53 molecular weight 53 kDa
- PUMA molecular weight 53 kDa
- the P53 protein is labeled ubiquitin by MDM2 protein and degraded by proteasome.
- Nutlin-3 ⁇ (molecular weight 581.49), known as an anticancer agent, binds to this MDM2 and inhibits p53-MDM2 interaction to increase p53 pathway activity. to be. Therefore, as a method for inhibiting Mycobacterium tuberculosis with p53 as a target, Nutlin-3 ⁇ alone or in combination with existing anti-tuberculosis therapeutics may be used.
- the present invention contributes to the activation of macrophages using Nutlin-3 ⁇ , which induces expression of p53 or induces p53 activity, to provide a method for preventing and effectively treating tuberculosis, which has a different mechanism of action and relatively fewer side effects.
- the present invention is to provide a pharmaceutical composition for preventing and treating tuberculosis comprising a Nutlin-3 ⁇ compound as an active ingredient.
- the Nutlin-3 ⁇ compound thus provided is characterized by overexpressing p53, and the overexpressed p53 inhibits the growth of Mycobacterium tuberculosis by inducing apoptosis of macrophages infected with Mycobacterium tuberculosis.
- the anti-tuberculosis agent used herein may be at least one selected from the group consisting of Rifampicin, Isoniazid, Ethambutol, and Pyrazinamide.
- the present invention utilizes the function of Mycobacterium tuberculosis of Nutlin-3 ⁇ , which is not known at all, it can be expected to have a prophylactic and therapeutic effect against Mycobacterium tuberculosis having multidrug resistance with respect to existing drugs.
- the growth of latent Mycobacterium tuberculosis can be suppressed, so that latent Mycobacterium tuberculosis can be removed when used alone or in combination with a conventional medicine.
- Figure 2 is a protein expression electrophoresis picture by western blotting showing p53 expression and Caspase-3 activity according to Nutlin-3 ⁇ concentrations treated in Mycobacterium tuberculosis-infected macrophages.
- 3 is a graph showing that the number of Mycobacterium tuberculosis in macrophages is significantly reduced by Nutlin-3 ⁇ treatment.
- 4 and 5 are graphs showing that the number of Mycobacterium tuberculosis in macrophages is significantly reduced by the combination of antituberculosis therapeutic agents (isoniazid, rifampicin, pyrazinamide, ethambutol) and Nutlin-3 ⁇ .
- antituberculosis therapeutic agents isoniazid, rifampicin, pyrazinamide, ethambutol
- Nutlin-3 ⁇ are graphs showing that the number of Mycobacterium tuberculosis in macrophages is significantly reduced by the combination of antituberculosis therapeutic agents (isoniazid, rifampicin, pyrazinamide, ethambutol) and Nutlin-3 ⁇ .
- FIG. 6 is a graph showing a significant increase in Mycobacterium tuberculosis survival in mice lungs with p53-deficient macrophage.
- FIG. 7 is a graph showing that the number of Mycobacterium tuberculosis in lung tissue is significantly decreased when pneumoniae-infected mice are intraperitoneally injected with Nutlin-3a (10 mg / kg / day).
- FIG. 8 is a graph showing that the expression of p53 in the macrophage of tuberculosis patients is significantly lower than that of healthy macrophage.
- FIG. 9 is a graph showing that the number of Mycobacterium tuberculosis in cells is significantly reduced when p53 activity is increased through Nutlin-3a.
- the present invention was first identified that the Nutlin-3 ⁇ compound has an effect of preventing or treating Mycobacterium tuberculosis through p53 overexpression and acting on apoptosis of macrophages.
- the present invention comprises a Nutlin-3 ⁇ compound as an active ingredient. It is characterized by providing a composition for preventing or treating Mycobacterium tuberculosis.
- 'Nutlin-3 ⁇ ' is a small molecule compound that binds to MDM2 and inhibits binding between MDM2 and p53 protein, and is known for its anticancer effect, and its chemical structure is shown in FIG. 1. More specifically, Nutlin-3 ⁇ is a small molecule compound that binds to MDM2 and inhibits binding between MDM2 and p53 protein. It is an anticancer drug currently being developed for the treatment of solid cancer. In detail, the MDM2 protein binds to the transactivation site of p53, a gene that inhibits cancer, and blocks the activation ability. The Nutlin-3 ⁇ compound has a molecular structure similar to that of p53.
- Nutlin-3 ⁇ compound is only known as an anticancer drug that is currently being developed in the clinic, and there is no report on the effect that it has on the treatment of tuberculosis.
- the present inventors have completed the present invention by confirming that Nutlin-3 ⁇ compound can improve tuberculosis through a mechanism of activating p53.
- Example 1 of the present invention when the Nutlin-3 ⁇ compound was injected into Bone marrow-derived macrophages (BMDMs) cells, which are mouse-derived macrophages, the number of Mycobacterium tuberculosis bacteria was significantly reduced, resulting in an improvement in tuberculosis. It could be confirmed.
- BMDMs Bone marrow-derived macrophages
- Example 2 of the present invention when used in combination with the existing anti-tuberculosis agent was confirmed to show an effect of significantly higher tuberculosis bacteria compared to the use of the existing anti-tuberculosis agent alone.
- Nutlin-3 ⁇ compound is effective in improving tuberculosis
- the composition of the present invention comprising it as an active ingredient can be usefully used in the prevention or treatment for tuberculosis.
- Tuberculosis in the present invention includes eye tuberculosis, skin tuberculosis, adrenal tuberculosis, kidney tuberculosis, epididymal tuberculosis, lymphatic tuberculosis, laryngeal tuberculosis, middle ear tuberculosis, intestinal tuberculosis, multidrug-resistant tuberculosis, pulmonary tuberculosis, tuberculosis, bone tuberculosis, throat tuberculosis, lymphatic tuberculosis We can include ruins, breast tuberculosis or spinal tuberculosis.
- existing anti-tuberculosis agents may include Rifampicin, Isoniazid, Ethambutol or Pyrazinamide used in Example 2 of the present invention.
- the term 'treatment' unless stated otherwise, reverses, alleviates, inhibits, or prevents the disease or condition to which the term applies, or one or more symptoms of the disease or condition, As used herein, the term 'treatment' refers to the act of treating when 'treating' is defined as above.
- BMDMs Bone marrow-derived macrophages
- Mycobacterium tuberculosis H37Ra non-pathogenic Mycobacterium tuberculosis
- Figure 2 shows the expression level of p53 protein expressed during Mycobacterium tuberculosis infection and the apoptosis marker Caspase-3 activity as a result of Western blot method in accordance with the increased treatment concentration of Nutlin-3 ⁇ (Fig. 1), a p53 inducing agent in macrophages infected with Mycobacterium tuberculosis. Increasing p53 and Caspas-3 activity was observed. ( ⁇ -actin is an internal control in Figure 2)
- FIG. 3 was treated with Nutlin-3 ⁇ (30 uM) in large macrophages infected with Mycobacterium tuberculosis and after 24 hours, the number of viable Mycobacterium tuberculosis cells was cultured in 7H10 agar medium for 14-21 days. As a result, the number of survival of the intracellular pathogenic Mycobacterium tuberculosis and nonpathogenic Mycobacterium tuberculosis was significantly reduced in the macrophages treated with Nutlin-3 ⁇ (30 uM) compared with the control group.
- Figures 4 and 5 show anti-tuberculosis treatment of isoniazid (10 ng / ml), rifampicin (10 ng / ml), pyrazinamide (100 ng / ml) or etambutol (100 ng / ml) during the infection of Mycobacterium tuberculosis bacteria. And Nutlin-3 ⁇ (30 uM) in combination to inhibit the growth of mycobacterium tuberculosis.
- Macrophage cells infected with pathogenic Mycobacterium tuberculosis or non-pathogenic Mycobacterium tuberculosis were treated with antituberculosis treatment alone or in combination with Nutlin-3 ⁇ to determine the number of tuberculosis viable in cells after 24 hours.
- the experimental results showed that the number of intracellular tuberculosis bacteria decreased significantly when anti-TB treatment and Nutlin-3 ⁇ were used in combination with anti-TB treatment alone.
- FIG. 6 shows the number of viable Mycobacterium tuberculosis bacteria in lung tissue after intranasal infection of non-pathogenic Mycobacterium tuberculosis in a control (wild type) or macrophage-deficient p53 (p53 conditional knockout) mouse.
- wild type wild type
- macrophage-deficient p53 p53 conditional knockout
- FIG. 7 shows that the number of Mycobacterium tuberculosis in lung tissue was significantly reduced when p53 activity was increased by intraperitoneal injection of Nutlin-3a (10 mg / kg / day) into mice infected with non-pathogenic Mycobacterium tuberculosis via the nasal cavity.
- the expression of p53 in the macrophage of tuberculosis patients was significantly lower than that of healthy macrophage.
- Figure 9 was infected with non-pathogenic Mycobacterium tuberculosis in macrophage derived from the blood of healthy or tuberculosis patients, treated with Nutlin-3a (10 uM) and the number of intracellular Mycobacterium viability was measured. As a result, when the p53 activity was increased through Nutlin-3a, it was confirmed that the number of Mycobacterium tuberculosis in the cells was significantly reduced.
- the mycobacterium tuberculosis can be suppressed by increasing the expression of p53 in the cells. Therefore, when the composition according to the present invention (Nutlin-3 ⁇ ) is treated with Mycobacterium tuberculosis-infected cells as an active ingredient to control p53, that is, when the composition of the present invention is treated to Mycobacterium tuberculosis carriers, tuberculosis patients or patients with existing anti-tuberculosis drug resistance It can be expected to kill my tuberculosis bacteria.
- the statistical method used was Bonferroni's multiple comparison test, marked with * when p-value ⁇ 0.05, ** when p-value ⁇ 0.01, and *** when p-value ⁇ 0.001.
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- Medicinal Chemistry (AREA)
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- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
La présente invention concerne une composition pharmaceutique permettant de prévenir ou de traiter la tuberculose, comprenant comme principe actif un composé à base de Nutline-3α. Un composé à base de Nutline-3α, qui est un principe actif selon la présente invention, a pour effet d'inhiber la prolifération de Mycobacterium tuberculosis en induisant, par l'intermédiaire de la surexpression de p53, l'apoptose des macrophages qui ont été infectés par Mycobacterium tuberculosis. Ainsi, une méthode selon la présente invention comprenant le composé à base de Nutline-3α comme principe actif peut être utilisée de manière utile pour prévenir ou traiter la tuberculose.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20170047868 | 2017-04-13 | ||
| KR10-2017-0047868 | 2017-04-13 | ||
| KR1020180041520A KR102082285B1 (ko) | 2017-04-13 | 2018-04-10 | 세포내 결핵균 제어를 위한 Nutlin-3α (뉴트린-3α) 및 p53 발현 조절 조성물 또는 방법 |
| KR10-2018-0041520 | 2018-04-10 |
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|---|---|
| WO2018190680A1 true WO2018190680A1 (fr) | 2018-10-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2018/004350 WO2018190680A1 (fr) | 2017-04-13 | 2018-04-13 | NUTLINE-3α PERMETTANT DE MAÎTRISER MYCOBACTERIUM TUBERCULOSIS INTRACELLULAIRE, ET COMPOSITION ET MÉTHODE PERMETTANT DE RÉGULER L'EXPRESSION DE P53 |
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| WO (1) | WO2018190680A1 (fr) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112575078A (zh) * | 2020-12-30 | 2021-03-30 | 山东大学第二医院 | lncRNAs作为活动性肺结核病特异性标志物的应用 |
| US20210379057A1 (en) * | 2018-10-16 | 2021-12-09 | Massachusetts Institute Of Technology | Nutlin-3a for use in treating a mycobacterium tuberculosis infection |
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| KR20150128731A (ko) * | 2013-03-15 | 2015-11-18 | 보드 오브 리전츠, 더 유니버시티 오브 텍사스 시스템 | 누트린-3a 및 펩티드에 의한 폐 섬유증의 저해 |
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- 2018-04-13 WO PCT/KR2018/004350 patent/WO2018190680A1/fr active Application Filing
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