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Application of benzyloxycarbonyl-L-glutamic acid in preparing BLyS (B lymphocyte stimulator) antagonist

A technology of benzyloxycarbonyl and glutamic acid, which is applied in anti-inflammatory agents, non-central analgesics, bone diseases, etc., and can solve problems such as benzyloxycarbonyl-L-glutamic acid that have not yet been developed

Inactive Publication Date: 2016-11-09
TIANJIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no report on the use of benzyloxycarbonyl-L-glutamic acid in the preparation of BLyS antagonists

Method used

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  • Application of benzyloxycarbonyl-L-glutamic acid in preparing BLyS (B lymphocyte stimulator) antagonist
  • Application of benzyloxycarbonyl-L-glutamic acid in preparing BLyS (B lymphocyte stimulator) antagonist
  • Application of benzyloxycarbonyl-L-glutamic acid in preparing BLyS (B lymphocyte stimulator) antagonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1: BLyS-related small molecule compounds were screened out using computer simulation screening technology.

[0038] Acquisition of protein structure information: Download the BLyS protein structure (PDB ID: 1OQD and 1OQE) from the Protein Date Bank protein database (http: / / www.rcsb.org / pdb). Computational methods such as molecular dynamics were used to explore the interaction mechanism between BLyS and its natural receptors (BCMA, TACI, BR3) at the molecular level. According to the contribution of each amino acid residue to the binding energy, determine its key residues. figure 1 and figure 2 The key residues of the natural receptors of the BLyS target, and the binding pocket and key residues of the BLyS target are shown respectively.

[0039] Acquisition of Small Molecule Database: The small molecule database contains nearly 10,000 compounds with different structures, which mainly come from two ways: small molecules in the natural product database or commerc...

Embodiment 2

[0041] Example 2: Computer Analysis of Small Molecule Antagonists and BLyS Binding Mode.

[0042] CBz-L-glutamic acid (structure see Figure 4 ) and the molecular mechanism of BLyS, and analyze the key amino acid residues and key interactions between it and BLyS ( Figure 5 ). It was found that a benzene ring of CBz-L-glutamic acid was inserted into the conserved hydrophobic pocket of BLyS, forming hydrophobic interactions with His69, Leu70 and Ile92, and forming π-cation interactions with the side chains of Arg124 and Arg90 residues, which jointly strengthened CBz -The combination of L-glutamic acid and BLyS; the carboxyl groups on the two side chains form a salt bridge with Arg90; the oxygen on the benzyloxycarbonyl group and the carbonyl oxygen in the amino acid carboxyl group form a hydrogen bond interaction with the key residue Arg124 of BLyS , the OH in the amino acid carboxyl group forms a hydrogen bond with Y65.

Embodiment 3

[0043] Example 3: Competition ELISA to analyze the inhibitory effect of compounds on BLyS binding to TACI / BCMA protein.

[0044] If the compound CBz-L-glutamic acid can compete with TACI / BCMA for binding to the active pocket of BLyS, the added compound CBz-L-glutamic acid will inhibit the binding of BLyS to TACI / BCMA; on the contrary, if the compound CBz-L-glutamic acid Without BLyS binding, there is no competition with TACI / BCMA. Then the addition of compound CBz-L-glutamic acid has no effect on the binding of BLyS to TACI / BCMA. Therefore, the effect of the small molecule CBz-L-glutamate on blocking the binding of BLyS to the receptors TACI and BCMA was tested by competitive inhibition ELISA experiments.

[0045] First, perform ELISA for the combination of BLyS and TACI-Fc / BCMA-Fc according to the conventional ELISA method. Determine the concentration of TACI-Fc / BCMA-Fc used in the competitive inhibition ELISA experiment. The final determined concentration was 10 μg / mL. T...

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Abstract

The invention discloses an application of benzyloxycarbonyl-L-glutamic acid in preparing a BLyS (B lymphocyte stimulator) antagonist. A result of a competitive ELISA experiment indicates that the benzyloxycarbonyl-L-glutamic acid is capable of inhibiting bonding of the BLyS and TACI-Fc; and an inhibitory effect is positively correlated to the concentration of the benzyloxycarbonyl-L-glutamic acid; the benzyloxycarbonyl-L-glutamic acid is capable of inhibiting bonding of the BLyS and BCMA-Fc; and an inhibitory effect is positively correlated to the concentration of the benzyloxycarbonyl-L-glutamic acid. The benzyloxycarbonyl-L-glutamic acid can serve as a potential BLyS small-molecular antagonist.

Description

technical field [0001] The invention belongs to the field of biomedicine and relates to the use of benzyloxycarbonyl-L-glutamic acid as a BLyS antagonist. Background technique [0002] B lymphocyte stimulating factor (B lymphocyte stimulator, BLyS), also known as B cell activating factor (Bcell activating factor belonging to the TNF family, BAFF), is a member of the TNF family. It is continuously synthesized and secreted by monocytes and macrophages. BLyS can bind three receptors on the surface of B cells, B cell mature antigen (B cell mature antigen, BCMA), transmembrane activator and CAML conjugate (Transmembrane activator and CAML-interactor, TACI) and BAFF receptor 3 (BR3) . Receptor binding to BAFF reduces apoptosis of mature B cells. If BAFF is knocked out, mature B cells in mice are completely absent. Since BLyS plays an important role in the activation and proliferation of B lymphocytes, humoral immunity mediated by antibodies produced by B lymphocytes plays a ce...

Claims

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Application Information

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IPC IPC(8): A61K31/27A61P37/00A61P19/02A61P29/00
CPCA61K31/27
Inventor 魏静孙剑傅学钢郝霞飞
Owner TIANJIN UNIV
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