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Sugar-modified metal helical complex, preparation method thereof and application of complex as amyloid protein degradation device

A technology of amyloid and helical coordination, applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., can solve the problems of difficult phagocytosis, phagocytic cell damage, lysosome rupture, etc., and achieve the effect of stable physiological conditions

Pending Publication Date: 2022-04-29
CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the application of protein-targeted degradation technology to the removal of amyloid faces some challenges
First, as a typical "undruggable" protein, amyloid lacks effective small-molecule targeting ligands; not only that, large-sized abnormal protein aggregates are difficult to be effectively phagocytized by phagocytes; in addition, due to fibrosis hIAPP aggregation has The dense structure is difficult to be effectively hydrolyzed by lysosomal proteases, which may even lead to the rupture of lysosomes and the damage of phagocytes

Method used

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  • Sugar-modified metal helical complex, preparation method thereof and application of complex as amyloid protein degradation device
  • Sugar-modified metal helical complex, preparation method thereof and application of complex as amyloid protein degradation device
  • Sugar-modified metal helical complex, preparation method thereof and application of complex as amyloid protein degradation device

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preparation example Construction

[0031] A method for preparing a sugar-modified metal helical complex of the present invention specifically comprises the following steps:

[0032] Anhydrous FeCl 2 , 5-(prop-2-yn-1-yloxy)pyridinecarbaldehyde and 2-(2,2'-bipyridine-5-oxygen)-1-methylbenzylamine were dissolved in anhydrous methanol at room temperature After stirring for 36-72h (preferably 48h), cool naturally to room temperature, filter through a diatomaceous earth plug, and remove the solvent under vacuum to obtain the alkylated metal helical complex (purple solid product); dissolve the alkylated metal helical complex In methanol, add cuprous iodide and sugar azide, heat and reflux at 50-70°C (preferably 65°C) under nitrogen protection for 12-24h (preferably 18h); remove the copper salt by filtration to obtain a sugar-modified metal helical complex thing.

[0033] Wherein, the structural formula of the 5-(prop-2-yn-1-yloxy)pyridinecarbaldehyde is as follows:

[0034]

[0035] Preferably, the 2-(2,2'-bipyr...

Embodiment 1

[0057] The preparation of the metal helical complex of embodiment 1 sugar modification

[0058] 2.5 mg / mL of anhydrous FeCl 2 (1 equivalent), 4.5 mg / mL of 5-(prop-2-yn-1-yloxy)pyridinecarbaldehyde (1.5 equivalents), 9.5 mg / mL of R-2-(2,2'-bipyridine- 5-Oxo)-1-methylbenzylamine (1.5 equivalents) was dissolved in 10 mL of anhydrous methanol, stirred at room temperature for 48 h, the reaction mixture was naturally cooled to room temperature, filtered through a diatomaceous earth plug, and the solvent was removed under vacuum to obtain The purple solid product is the metal alkynylation helical complex; then the alkynylated metal helical complex (1 equivalent) is dissolved in methanol, cuprous iodide (0.1 equivalent) and azide sugar (4.5 equivalents) are added, nitrogen protection Heat and reflux at 65°C for 18 hours; after the reaction, remove the copper salt by filtration to obtain a sugar-modified metal helical complex with a structure of Λ1, and the structural formula is as fo...

Embodiment 2

[0067] Example 2 Application of sugar-modified metal helical complexes as amyloid degraders in inhibiting hIAPP aggregation

[0068] First, lyophilized hIAPP powder was dispersed in hexafluoroisopropanol and stored at -20°C. The dispersion was dried under a nitrogen atmosphere, the hIAPP peptide was redissolved in ultrapure water, with or without the sugar-modified metal helical complex prepared in Example 1, and incubated at 37°C for 24 hours. The effects of sugar-modified metal helical complexes on the aggregation morphology of hIAPP were examined by transmission electron microscopy.

[0069] Such as figure 2 As shown in a, both Δ1 and Δ1 significantly inhibited the abnormal aggregation of proteins. The effects of sugar-modified metal helical complexes on hIAPP aggregation were further confirmed by circular dichroism, as shown in figure 2 As shown in middle b, hIAPP alone transformed from α-helical structure (characteristic peak 205nm) to protein aggregates with β-sheet...

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Abstract

The invention relates to a sugar-modified metal helical complex, a preparation method thereof and application of the sugar-modified metal helical complex as an amyloid protein degradation device.The preparation method comprises the steps that anhydrous FeCl2, 5-(propyl-2-alkyne-1-yloxy) pyridylaldehyde and 2-(2, 2 '-bipyridine-5-yloxy)-1-methylbenzylamine are dissolved in absolute methyl alcohol, stirring is conducted for 1-2 h at the temperature of 50-60 DEG C, and then the sugar-modified metal helical complex is obtained; stirring at room temperature for 36-72 hours, naturally cooling to room temperature, filtering, removing the solvent to obtain an alkynylation metal helical complex, dissolving in methanol, adding cuprous iodide and azide sugar, and heating and refluxing at 50-70 DEG C for 12-24 hours under the protection of nitrogen; and filtering to remove the copper salt to obtain the sugar-modified metal helical complex. The invention can effectively inhibit abnormal aggregation of human islet amyloid polypeptide outside type II diabetes related cells, induce transport and degradation of macrophage lysosome of the human islet amyloid polypeptide, and relieve cell damage caused by abnormal aggregation of amyloid protein.

Description

technical field [0001] The invention belongs to the technical field of drug design for protein targeted degradation, and in particular relates to a sugar-modified metal helical complex, a preparation method thereof and an application as an amyloid degrader. Background technique [0002] The amyloid fibrosis aggregation (amyloidosis) of human islet amyloid polypeptide (hIAPP) is an important pathological feature of type 2 diabetes, and it is found to exist in the pancreas tissue of more than 90% of type 2 diabetes patients. Based on some observations listed below (including but not limited to), it is believed that the fibrosis of human amylin is closely related to the pathogenesis of type 2 diabetes: First, in some Asian type 2 diabetic patients there is a human amylin The genetic mutation S20G of the polypeptide (serine at position 20 is mutated to glutamic acid), this mutation can accelerate the fibrosis of human amylin, and can also cause familial and early-onset type II d...

Claims

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Application Information

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IPC IPC(8): C07H23/00C07H1/00A61P3/10
CPCC07H23/00C07H1/00A61P3/10
Inventor 曲晓刚刘镇旗
Owner CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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