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A kind of thioester staple peptide and its preparation method and application

A technology for ordering peptides and thioesters, which is applied in the field of peptides to avoid product isomerization

Active Publication Date: 2021-04-30
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the advantages of high efficiency, low toxicity and easy synthesis of DTCs compounds, they have become a research hotspot in the field of medicinal chemistry, but the application of DTCs in α-helical conformation-locked peptides has not been reported yet.

Method used

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  • A kind of thioester staple peptide and its preparation method and application
  • A kind of thioester staple peptide and its preparation method and application
  • A kind of thioester staple peptide and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1 Thioester stapled peptide synthesis

[0044] raw material

[0045]Buffer A: 6M Guanidine HCl, 100 mM Na 2 HPO 4 , pH=8.5;

[0046] Buffer B: 6M Guanidine HCl, 100 mM NaH 2 PO 4 , pH=2.5;

[0047] Table 3 Linear peptides

[0048]

[0049] Each of the linear peptides shown in Table 3 can be prepared by peptide solid phase synthesis (SPPS).

[0050] The following takes the linear peptide PS1-1-1 to prepare the thioester stapled peptide as an example for specific description, and the operations for preparing the thioester stapled peptide from the other linear peptides are the same.

[0051] synthetic route:

[0052]

[0053] Synthesis steps:

[0054] (a) Cys is removed to Dha

[0055] The linear peptide PS1-1-1 (50 mg) was dissolved in buffer B (3 mL), and then slowly dropped into buffer A (47 mL) dissolved in 2,5-dibromoadipamide (75 mg) at room temperature. After stirring overnight, HPLC detected that the reaction was complete, purified by prepa...

Embodiment 2

[0061] Example 2 Fluorescence polarization binding experiment

[0062] First, TAMRA-NHS (tetramethylrhodamine-N-hydroxythiosuccinimide) was covalently linked to the N-terminal amino group of PMI (TSFAEYWNLLSP), and a fluorescent label with TAMRA as the fluorophore was obtained. The peptide PMI-TAMRA followed by determination of the binding constants of PMI-TAMRA to MDM2 and MDMX were 0.62 nM and 0.72 nM, respectively. In order to verify the specificity of this method, the competitive binding constant K of the complex system of PMI-TAMRA and MDM2 or MDMX of PMI that is not labeled with fluorescence was determined i . In addition, as a control, the competitive binding constant K of Nutlin-3 for MDM2 or MDMX was also determined i , 5.1 nM and 1.54 μM, respectively, which are in agreement with the reported K i The values ​​are basically the same. K i The smaller the value, the higher the binding ability, and the better the binding ability of the modified polypeptide PMI of th...

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Abstract

The invention discloses a thioester-stapled peptide, which is characterized in that the peptide chain contains a fragment shown by formula (I) or formula (II), and the fragment is located at the end or middle section of the peptide chain, the formula (I ) and formula (II), each y is independently selected from one of the 20 protein amino acids. The invention also discloses a method for preparing the thioester staple peptide. The present invention introduces the DTC synthesis reaction into the preparation of α-helical conformation-locked polypeptides for the first time, and stabilizes the α-helical conformation of the polypeptide by forming dithiocarbamate linkage arms on the side chains of the peptides to achieve the purpose of conformational locking. This peptide conformational locking strategy can effectively avoid problems such as product isomerization, poor water solubility and dependence on solid-phase cyclization.

Description

technical field [0001] The invention relates to the technical field of polypeptides, in particular to a thioester stapled peptide and a preparation method and application thereof. Background technique [0002] The α-helix structure is an important protein epitope in nature, and many important protein-protein interactions and protein recognition in organisms are mediated by the α-helix structure. α-helical conformation-locked polypeptides (generally, polypeptides that lock the α-helix conformation by chemical means) are important tool molecules for regulating intracellular PPIs. The development of α-helical conformation-locked polypeptide strategies can not only provide PPIs as targets for drug design New active molecules can also provide molecular probes for the study of the function and structure of a protein. On the one hand, conformation-locked polypeptides can bind polypeptides through non-natural chemical bonds to resist the degradation of proteases, and achieve the ef...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/08C07K1/107A61K38/10A61P35/00
Inventor 李翔邹燕胡宏岗陆五元
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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