Compound capable of killing trypanosoma brucei, and application thereof in treating trypanosoma brucei

A technology of Trypanosoma brucei and compounds, applied in the field of biopharmaceuticals, can solve problems such as poor specificity, low affinity, and unclear mechanism, and achieve the effects of high affinity, high-efficiency killing, and clear mechanism of inhibitor action

Active Publication Date: 2017-12-08
UNIV OF SCI & TECH OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Compound I-BET151 has been used as an inhibitor of acetylated lysine binding domain in the treatment of African trypanosomiasis 2 , but there are disadvantages such as poor specificity, low affinity, and unclear mechanism

Method used

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  • Compound capable of killing trypanosoma brucei, and application thereof in treating trypanosoma brucei
  • Compound capable of killing trypanosoma brucei, and application thereof in treating trypanosoma brucei
  • Compound capable of killing trypanosoma brucei, and application thereof in treating trypanosoma brucei

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 The compound GSK2801 inhibits the binding of N-terminal polyacetylated H2AZ to the acetylated lysine binding domain of TbBDF2

[0037] (1) The acetylated lysine-binding domain of TbBDF2 can bind N-terminal polyacetylated H2AZ

[0038] Using protein affinity purification and LC-MS 4 Identification of histones bound by TbBDF2. Harvest 0.5 liter of cultured TbBDF2 cells with PTP purification tag at the carbon end and resuspend in lysis buffer (20mM HEPES pH 7.4, 100mMNaCl, 1mM MgCl 2, 2% glycerol, 1 mM EDTA, 0.1% Triton X-100, 0.2% NP-40, protease inhibitor cocktail (Roche)), using the method of pressure disruption (Beijing Changliu Scientific Instrument Company, FB-110X) to disrupt the cells, Cell lysates were incubated with 200 microliters of immunoglobulin-conjugated agarose beads (GE) at 4°C for 2 hours. Then the agarose beads were washed twice with lysis buffer, and finally the protein mixture was eluted with 0.1M glycine. The samples were separated by 4...

Embodiment 2

[0051] Example 2 The compound GSK2801 can cause changes in the localization of TbBDF2 in Trypanosoma brucei

[0052] The cell line with EYFP-tagged TbBDF2 was treated with DMSO (as a negative control) and 10 micromolar GSK2801 for 48 hours, and then the intracellular localization was observed using a fluorescence microscope. In the control group, TbBDF2 was mainly localized in the nucleolus, However, the localization of TbBDF2 in the cells treated with GSK2801 changed from the nucleolus to the entire nucleus, and the same phenomenon also occurred in the cells treated with 20 μM. This shows that the small molecule GSK2801 can lead to changes in the localization of TbBDF2 in Trypanosoma brucei cells, thereby inducing the loss of function of TbBDF2 protein.

Embodiment 3

[0053] Example 3 Compound GSK2801 can effectively kill Trypanosoma brucei

[0054] Under the same DMSO concentration conditions, 427 cells were treated with 0, 10, 20, 30, 40 micromolar GSK2801, and cell counts were performed every day. It was found that after treating the 427 cell line with a concentration of 20-40 μM GSK2801, it can induce obvious growth inhibition of 427 cells and a large number of cell death in 24-96 hours, see Figure 4 a.

[0055] The small molecule GSK2801 was diluted according to the concentration gradient ((35, 30, 25.6, 12.8, 6.4, 3.2, 1.6, 0.8, 0.4, 0.2, 0.1, 0 micromolar)) and added to the 96-well plate, and then added to the well containing 2× 10 5 200 microliters of medium of 427 cells were cultured for 72 hours, and 20 microliters of resazurin (22.88 mg / ml) was added to each well, and detected after incubation for 6 hours. The monitoring data were calculated with OriginPro 8.0 software according to the Boltzmann function. Finally, the half-i...

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Abstract

The invention relates to a compound capable of killing trypanosoma brucei, and application thereof in treating trypanosoma brucei. The compound is GSK2801, specifically targets a TbBDF2 acetylated lysine binding domain, has high affinity with the TbBDF2 acetylated lysine binding domain, and can be used for efficiently killing trypanosoma brucei.

Description

technical field [0001] The invention belongs to the technical field of biopharmaceuticals, and relates to a compound capable of killing trypanosome brucei, a pharmaceutical composition containing the compound, and an application thereof in the preparation of a medicament for treating trypanosomiasis. The compound of the present invention can be developed as a precursor molecule of a drug for treating African trypanosomiasis or can be directly used for the treatment of trypanosomiasis. Background technique [0002] Trypanosoma brucei is a single-celled eukaryotic parasite, including three subspecies of Trypanosoma brucei, Trypanosoma brucei gambiae, and Trypanosoma brucei Rhodesia, which can infect humans through the vector tsetse fly And other animals, causing human sleeping sickness (sleeping sickness) and animal Nagana disease (nagana disease), collectively referred to as African trypanosomiasis. Human infection with Trypanosoma brucei has a high mortality rate in the lat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/437A61P33/02
CPCC07D471/04
Inventor 廖善晖杨晓涂晓明
Owner UNIV OF SCI & TECH OF CHINA
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