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Histidine-containing polypeptide compound modified by c-h alkylation promoted by visible light and preparation method thereof

A compound and visible light technology, applied in the field of histidine-containing polypeptides and their preparation, to achieve good compatibility and avoid the effect of reducing activity

Active Publication Date: 2022-03-08
SHANGHAI JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are currently no reports of selective Minisci reactions for histidine residues in peptides or proteins under mild conditions

Method used

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  • Histidine-containing polypeptide compound modified by c-h alkylation promoted by visible light and preparation method thereof
  • Histidine-containing polypeptide compound modified by c-h alkylation promoted by visible light and preparation method thereof
  • Histidine-containing polypeptide compound modified by c-h alkylation promoted by visible light and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-10

[0081] Screening of reaction solvents:

[0082]

[0083] Peptide 6 (2.0 μmol, 1 equiv.), DHP-a (20.0 μmol, 10 equiv.), deoxygenated TFA (1.49 μL, 20.0 μmol, 10 equiv.) and deoxygenated solvent (0.2 mL , 10 mM) into a 1 mL dry micro-reaction vial equipped with a magnetic stirrer, sealed and taken out from the argon atmosphere glove box. The schematic diagram of the preparation of the reaction is shown in figure 1 As shown, irradiate with two 10W blue LED lamps (the distance between the sample and the lamp is 3cm, and the cooling fan keeps the temperature at about 35°C) for 3 hours, add glacial ether to the reaction solution, and carefully discard the upper liquid after centrifugation. After drying under pressure, LCMS analysis was performed. The second and third cycles were carried out in the same manner as Example 5. The difference of embodiment 1-10 is only the difference of reaction solvent, specifically as shown in table 1, product 6-a structural analysis is as follow...

Embodiment 17-20

[0096] Screening of reagent equivalents in reactions:

[0097]

[0098] Peptide 6 (2.0 μmol, 1 equiv.), DHP-a, deoxygenated TFA and deoxygenated TFE (0.2 mL, 10 mM) were added to a 1 mL dry microreaction vial equipped with a magnetic stir bar in the glove box , sealed and taken out from the argon atmosphere glove box. Irradiate with two 10W blue LED lamps (the sample is 3cm away from the lamp, and the cooling fan keeps the temperature at about 35°C) for 3 hours. Glacial diethyl ether was added to the reaction solution, the upper layer liquid was carefully discarded after centrifugation, and the precipitate was dried under reduced pressure for LCMS analysis. The difference between Examples 17-20 is that the equivalents of DHP-a and TFA used in the reaction are different, as shown in Table 3.

[0099] The screening of DHP-a and TFA equivalent in table 3 reaction

[0100]

[0101] a: LCMs Yleld

[0102] It can be seen from the above results that the use of different equ...

Embodiment 21-22

[0104] Screening of reaction concentration:

[0105]

[0106] In the glove box, peptide 6 (2.0 μmol, 1 equiv.), DHP-a (20.0 μmol, 10 equiv.), deoxygenated TFA (1.49 μL, 20.0 μmol, 10 equiv.) and deoxygenated TFE were added to Put it in a 1mL dry micro reaction vial equipped with a magnetic stirrer, seal it and take it out of the argon atmosphere glove box. Irradiate with two 10W blue LED lamps (the sample is 3cm away from the lamp, and the cooling fan keeps the temperature at about 35°C) for 3 hours. Glacial diethyl ether was added to the reaction solution, the upper layer liquid was carefully discarded after centrifugation, and the precipitate was dried under reduced pressure for LCMS analysis. The difference between Examples 21-22 is only the difference in reaction concentration, as shown in Table 4.

[0107] Screening of table 4 reaction concentration

[0108]

[0109] a: LCMS Yield

[0110] From the above results, it can be seen that the reaction concentration has ...

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Abstract

The present invention relates to a histidine-containing polypeptide modified by visible light-promoted C-H alkylation and a preparation method thereof. The preparation method is as follows: the compound of formula I, the compound of formula II and the acid undergo intermolecular Minisci alkylation reaction under the condition of visible light irradiation to generate the compound of formula III modified by the imidazole ring of histidine residue in the polypeptide or protein. This method is the first to achieve highly selective post-transcriptional modification (PTM) of the C-2 position of the imidazole ring of histidine residues, which simplifies the modification method of unnatural amino acids in peptides and proteins, and overcomes the traditional modification methods of peptides and proteins. The existing limitations of amino acid and functional group incompatibility have broadened new methods for post-transcriptional modification of polypeptides or proteins. This method provides an efficient and novel method for protein and polypeptide drugs to establish new drug molecular libraries and high-throughput active drug screening through post-transcriptional modification.

Description

technical field [0001] The invention belongs to the field of polypeptide chemical synthesis, and in particular relates to a histidine-containing polypeptide modified by C-H alkylation promoted by visible light and a preparation method thereof. Background technique [0002] As a very important class of biomolecules, peptides play an indispensable role in living systems. Natural or synthetic peptides have been successfully used as pharmaceutical molecules and play an integral role in the development of new drugs. Compared with total synthesis, the site-selective modification of existing peptides can simplify the synthesis steps, thus making the activity research of peptides more direct and efficient. Many effective peptide modification methods have been developed, but most of them are limited to some nucleophilic residues, such as cysteine ​​(Cys) and lysine (Lys). Breaking free from such constraints would greatly expand the means for functionalizing peptides. This paper in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/00C07K7/06C07K1/02
CPCC07K14/00C07K7/06
Inventor 王平陈小平叶发荣
Owner SHANGHAI JIAOTONG UNIV
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