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Novel application of Plerixafor in preparation of drugs for treating or preventing diseases related to GSDMD protein

A technology of plerixafor and disease, which is applied in the field of medicine, can solve the problems such as the use of infectious inflammatory diseases that have not been reported, and achieve the effects of reducing clinical scores and morbidity, reducing secretion, and increasing the number of monocytes

Active Publication Date: 2020-05-22
NANJING DRUM TOWER HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But there is no report on its use in the prevention and treatment of infectious inflammatory diseases and autoimmune diseases

Method used

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  • Novel application of Plerixafor in preparation of drugs for treating or preventing diseases related to GSDMD protein
  • Novel application of Plerixafor in preparation of drugs for treating or preventing diseases related to GSDMD protein
  • Novel application of Plerixafor in preparation of drugs for treating or preventing diseases related to GSDMD protein

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1: Plerixafor can reduce the cytotoxicity and IL-1β secretion of immortalized mouse bone marrow-derived macrophages

[0044] 1.1) Cell culture

[0045] Immortalized mouse bone marrow-derived macrophages (iBMDMs) were cultured in DMEM medium containing 10% FBS

[0046] 1.2) iBMDMs grouping and processing

[0047] On the first day, the cells were seeded on a 96-well plate, 5*10 per well 4 cells;

[0048] On the second day, the iBMDMs in the 96-well plate were randomly divided into UN group (control group), LPS group, LPS+ATP group, plerixafor 5uM group, plerixafor 25uM group and plerixafor 100uM group, each The iBMDMs in each well were centrifuged to remove the supernatant, and then the DMEM medium containing 10% FBS without LPS was added to the UN group, and the other five groups were added with LPS (100ng / ml) of DMEM medium containing 10% FBS in 5% CO 2 After culturing in the incubator at 37°C for three hours, the iBMDMs of each group were treated as follo...

Embodiment 2

[0059] Example 2: Plerixafor can reduce the cytotoxicity of human mononuclear macrophage cell line

[0060] 2.1) Cell culture

[0061] A human mononuclear macrophage cell line (THP-1) was cultured in RPMI medium (Gibco) containing 10% FBS.

[0062] 2.2) THP-1 grouping and processing

[0063] On the first day, the cells were divided into 96-well plates, 5*10 per well 4 cells

[0064] On the second day, THP-1 in 96-well plate was randomly divided into UN group (control group), LPS group, LPS+ATP group, plerixafor 5uM group, plerixafor 25uM group and plerixafor 100uM group , 6 replicate wells per group, 5*10 per well 4 For each well, add phorbol 12-myristate-13-acetate (phorbol-12-myristate-13-acetate, PMA) to a final concentration of PMA of 100 nM to stimulate cell differentiation and adhesion in each well. After 4 hours of differentiation treatment, the supernatant was removed, then the UN group was added the RPMI medium containing 10% FBS without LPS, and the other five g...

Embodiment 3

[0075] Example 3: Plerixafor can reduce the cytotoxicity of mouse bone marrow-derived macrophages

[0076] 3.1) Cell culture

[0077] Use DMEM medium containing 20% ​​L929 cell (mouse fibroblast) culture supernatant to cultivate mouse bone marrow-differentiated macrophages (BMDMs). L929 cell culture supernatant was cultured and differentiated in DMEM medium for 4 days; on the fifth day, BMDMs cells were seeded on 96-well plates, 5*10 per well 4 cells, and the culture medium was replaced with DMEM medium containing 10% FBS to continue culturing;

[0078] 3.2) BMDMs grouping and processing

[0079] Step 3.1) On the sixth day of cell culture, the BMDMs in the 96-well plate in 3.1) were randomly divided into UN group, LPS group, LPS+ATP group, plerixafor 1uM group, plerixafor 2uM group and plerixafor 10uM group, 6 replicate wells in each group, 5*10 in each well 4 Remove the supernatant from the BMDMs in each well, then add DMEM medium containing 10% FBS without LPS to the UN ...

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Abstract

The invention belongs to the technical field of medicine, and particularly relates to novel application of Plerixafor in preparation of drugs for treating or preventing diseases related to GSDMD protein. The affinity between Plerixafor and the human GSDMD protein is detected through an MST technology, and the effects of Plerixafor on the mortality of macrophages of humans and mice and secretion amount of IL-1 beta inflammatory factors and the control effect of Plerixafor on mouse EAE and mouse sepsis are evaluated through pharmacodynamic tests. It is shown that the mortality of macrophages ofhumans and mice can be reduced significantly by Plerixafor, secretion of the IL-1 beta inflammatory factors can be reduced, and Plerixafor has a high binding force on the human GSDMD protein; meanwhile, the symptoms of mouse EAE can be alleviated significantly, and the survival rate of sepsis model mice can be improved; and it is indicated that Plerixafor is a human GSDMD protein-targeting drug, the symptoms of MS and sepsis can be alleviated through prevention of cell pyrolysis and inflammatory factor release, and therefore Plerixafor can be used as novel and optional drugs for prevention ortreatment of MS, sepsis and other autoimmune diseases and infectious inflammatory diseases, and has a broad development and application value.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to the application of plerixafor in the preparation of drugs for preventing or treating GSDMD protein-related diseases. Background technique [0002] Gasdermin D protein (GSDMD) belongs to the gasdermin protein family, which also includes GSDMA, GSDMB, GSDME, DFNB59 and other members. Under normal circumstances, the N-terminal and C-terminal domains interact tightly, making GSDMD in an inactive autoinhibitory state. After being cleaved by inflammatory caspases, GSDMD-N-terminal can cause pyroptosis, which is essentially a In this type of programmed cell necrosis, the oligomerization of GSDMD-N terminal forms holes in the cell membrane, and the cells rapidly expand and rupture, which eventually leads to the release of a large amount of cell contents and a strong inflammatory response. Therefore, GSDMD protein is pathogenic in various immune diseases including multiple sc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/395A61P31/00A61P31/04A61P37/02A61P25/00A61P19/02A61P29/00
CPCA61K31/395A61P31/00A61P31/04A61P37/02A61P25/00A61P19/02A61P29/00
Inventor 张存金徐运朱立文
Owner NANJING DRUM TOWER HOSPITAL
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