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Use of a compound and its derivatives for treating pneumococcal infectious diseases

A pneumococcus and compound technology, applied in the direction of boron compound active ingredients, antibacterial drugs, etc., to achieve the effect of low toxicity and inhibiting the growth of pneumococcus

Active Publication Date: 2017-04-19
CENT FOR EXCELLENCE IN MOLECULAR CELL SCI CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, biochemical results showed that AN2690 can significantly inhibit the catalytic activity of human cytoplasmic LeuRS (hcLeuRS), therefore, this compound should only be used topically

Method used

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  • Use of a compound and its derivatives for treating pneumococcal infectious diseases
  • Use of a compound and its derivatives for treating pneumococcal infectious diseases
  • Use of a compound and its derivatives for treating pneumococcal infectious diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1 The inhibitory effect of ZCL039 on SpLeuRS

[0026] 1. Inhibitory effect of ZCL039 on aminoacylation of SpLeuRS

[0027] 1.1. Experimental materials

[0028] 1) ZCL039: It can be prepared by referring to the preparation steps of compound 34 in Ding, D.Z., et al. (2010). Discovery of Novel Benzoxaborole-Based Potent Antitrypanosomal Agents. ACS Med. Chem. Lett., 1, 165–169.

[0029] 2) Preparation of pneumococcal leucyl-tRNA synthetase (SpLeuRS): Using pneumococcal genomic DNA as a template and using P1 / P2 (Table 1) as upstream and downstream primers, the SpLeuRS coding gene (NC_011900 .1). The PCR product was digested with Nco I / Xho I and inserted into the corresponding site of the pET30a vector, and the N-terminus was screened to carry His 6 Positive clones of the tag-encoding gene: pET30a-splrs. It was transformed into E.coli BL21(DE3) host bacteria for expression, the induced expression of protein was carried out according to the conventional method in ...

Embodiment 2

[0047] Example 2 Enzyme-catalyzed kinetics research

[0048] 1. Experimental method

[0049] 1) The aminoacylation reaction catalyzed by ZCL039 and substrate ATP:SpLeuRS was carried out at 37°C. In order to determine the kinetic constant of ATP inhibition in the presence of ZCL039, the reaction system contained different concentrations of ATP (0.3mM, 0.5 mM, 1.0mM, 1.5mM, 2.0mM, 4.0mM, 8.0mM), 40μM[ 3 H] Leucine (Leu), 10 μM tRNA Leu , 5 nM of SpLeuRS, and three concentrations of ZCL039 (0, 2 μM, 8 μM). Before the reaction, will contain SpLeuRS, [ 3 H] leucine, tRNA Leu And the reaction system with a certain concentration of ZCL039 was incubated at room temperature for 20 minutes, then ATP was used to start the reaction, and the reaction was terminated after 2 minutes to detect the amount of product produced. Obtain the curve of product generation rate and substrate concentration relation according to the Mie equation fitting, carry out nonlinear fitting to it again and o...

Embodiment 3

[0054] Example 3 Relationship between ZCL039 and SpLeuRS active center CP1

[0055] 1. Interaction of ZCL039 with wild-type SpLeuRS and SpLeuRS lacking CP1 active center

[0056] 1) Experimental material: CP1 deletion mutant (delCP1) of SpLeuRS. The construction method is as follows: using pET30a-splrs prepared in Example 1 as a template, according to the method of KOD-plus mutation kit (TOYOBO), using P3 / P4 (Table 1) The primers were used for inverse PCR amplification to construct the pET30a-splrs-delCP1 vector, in which Lys226-Thr411 (YP_002510309.1) in the CP1 domain of SpLeuRS was replaced by a sequence encoding the nonapeptide KEEIDGKIT. The gene expression and protein purification of the CP1 deletion mutant were performed according to the expression and purification of SpLeuRS in Example 1; SpLeuRS wild type (WT): the SpLeuRS prepared in Example 1 was used as the wild type control.

[0057] 2) Experimental method:

[0058] The reaction system is shown in Table 4. The 5...

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Abstract

The invention relates to the field of pharmaceutical chemistry, and particularly relates to a novel compound for treating pneumococcal infectious diseases, and use of the compound. According to the compound disclosed by the invention, the structural general formula is as shown in the formula I. The compound disclosed by the invention, especially ZCL039 can be applied to preparing a leucyl-tRNA synthetase inhibitor, and medicines for treating pneumococcal infectious diseases, and can be used for inhibiting or killing pathogenic microorganisms such as pneumococcus and the like. The compound disclosed by the invention has the advantage of activity of resisting pneumococcus, has a strong function of inhibiting SpLeuRS, is low in toxicity on human cells, and provides a new path for treatment of the pneumococcal infectious diseases.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a novel compound for treating pneumococcal infectious diseases and its application. Background technique [0002] Pneumococcus is the main pathogen of bacterial pneumonia. It can also cause a variety of infectious diseases such as otitis media, meningitis, bacteremia and sepsis, leading to high morbidity and mortality worldwide. Prompt and reasonable antibiotic treatment can effectively save the patient's life. Sulfamethoxazole and penicillin are two main types of effective antibacterial agents against pneumococcus, which are clinically used in the treatment of patients with pneumococcal infection. However, in recent years, clinical isolates have become more and more resistant to penicillin, which poses a great threat to human health. Therefore, it is urgent to develop new anti-pneumococcal drugs that are not restricted by existing drug-resistant bacteria. [0003] Leucyl-tRN...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/69A61P31/04
Inventor 王恩多胡庆华刘如娟
Owner CENT FOR EXCELLENCE IN MOLECULAR CELL SCI CHINESE ACAD OF SCI
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