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Thioester stapled peptide, preparation method and application thereof

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

Active Publication Date: 2018-01-19
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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  • Thioester stapled peptide, preparation method and application thereof
  • Thioester stapled peptide, preparation method and application thereof
  • Thioester stapled peptide, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1 Synthesis of Thioester Stapled Peptide

[0043] raw material

[0044] Buffer A: 6M Guanidine Hydrochloride, 100mM Na 2 HPO4 ,pH=8.5;

[0045] Buffer B: 6M Guanidine Hydrochloride, 100mM NaH 2 PO 4 ,pH=2.5;

[0046] Table 3 Linear peptides

[0047]

[0048] The linear peptides shown in Table 3 can be prepared by solid-phase polypeptide synthesis (SPPS).

[0049] The preparation of thioester-stapled peptide by linear peptide PS1-1-1 is described below as an example, and the operation of preparing thioester-stapled peptide by other linear peptides is the same.

[0050] synthetic route:

[0051]

[0052] Synthetic steps:

[0053] (a) Cys is removed to Dha

[0054] Dissolve linear peptide PS1-1-1 (50 mg) in buffer B (3 mL), then slowly drop into buffer A (47 mL) dissolved with 2,5-dibromoadipamide (75 mg), at room temperature After stirring overnight, HPLC detected that the reaction was complete, purified by preparative liquid phase and lyophilized ...

Embodiment 2

[0060] Embodiment 2 Fluorescence polarization binding experiment

[0061] First, TAMRA-NHS (tetramethylrhodamine-N-hydroxysulfosuccinimide) was covalently linked to the N-terminal amino group of PMI (TSFAEYWNLLSP), and a fluorescent label with TAMRA as the fluorescent group was obtained. The peptide PMI-TAMRA was subsequently determined to have binding constants of 0.62 nM and 0.72 nM for PMI-TAMRA to MDM2 and MDMX, 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 was determined without fluorescent labeling i . In addition, as a control, the competitive binding constant K of Nutlin-3 to MDM2 or MDMX was determined at the same time i , are 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 it is, the higher the binding ability is, and the modified polypeptide PMI of the present invention has ...

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Abstract

The invention discloses a thioester stapled peptide. The thioester stapled peptide is characterized in that a peptide chain contains segments shown as a formula (I) or a formula (II) in the description, wherein the segments are positioned at end parts or middle parts of the peptide chain. In the formula (I) and the formula (II), each y is separately selected from one of 20 protein amino acids. Theinvention further discloses a method for preparing the thioester stapled peptide. According to the method, DTC (Dithiocarbamates) synthesis reaction is introduced into the preparation of an alpha-helical conformation-locked polypeptide, an dithiocarbamate link arm is formed on a side chain of a peptide segment in order to stabilize the alpha-helical conformation of the polypeptide and fulfill theaim of locking the conformation. According to the polypeptide conformation locking strategy, the problems of product isomerization, poor water solubility, dependence on solid-phase cyclization and the like can be effectively solved.

Description

technical field [0001] The invention relates to the technical field of polypeptides, in particular to a thioester-stapled peptide and its preparation method and application. Background technique [0002] The α-helix structure is an important protein epitope in nature. Many important protein-protein interactions and protein recognition in organisms are mediated by the α-helix structure. α-helical conformation-locked polypeptides (generally, polypeptides locked in α-helical conformation by chemical means) are important tool molecules for regulating PPIs in cells. New active molecules can also provide molecular probes for the study of the function and structure of a certain protein. On the one hand, the conformationally locked polypeptide can bind the polypeptide through non-natural chemical bonds to resist the degradation of proteases and achieve the effect of improving the stability in vivo. On the other hand, a major weakness of polypeptide drugs is that it is difficult to...

Claims

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Application Information

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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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