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Histidine-containing polypeptide modified by C-H alkylation promoted by visible light and preparation method of polypeptide

A visible light, C-H technology

Active Publication Date: 2020-05-01
SHANGHAI JIAO TONG 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 modified by C-H alkylation promoted by visible light and preparation method of polypeptide
  • Histidine-containing polypeptide modified by C-H alkylation promoted by visible light and preparation method of polypeptide
  • Histidine-containing polypeptide modified by C-H alkylation promoted by visible light and preparation method of polypeptide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-10

[0082] Screening of reaction solvents:

[0083]

[0084] 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. After drying by 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 follows Figure 2-8 shown.

[0085] The screening of table 1 reaction solvent

[0086]

[0087] a: LCMS Yiel...

Embodiment 17-20

[0097] Screening of reagent equivalents in reactions:

[0098]

[0099] 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 for 3 hours 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). 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.

[0100] The screening of DHP-a and TFA equivalent in table 3 reaction

[0101]

[0102] a: LCMS Yield

[0103] It can be seen from the above results that the use o...

Embodiment 21-22

[0105] Screening of reaction concentration:

[0106]

[0107] 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 In a 1mL dry micro reaction vial equipped with a magnetic stirrer, take it out of the argon atmosphere glove box after sealing. Use 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.

[0108] Screening of table 4 reaction concentration

[0109]

[0110] a: LCMS Yield

[0111] From the above results, it can be seen that the reaction concentration has little effect on...

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Abstract

The invention relates to a histidine-containing polypeptide modified by C-H alkylation promoted by visible light and a preparation method of the polypeptide. The preparation method comprises the following steps: carrying out intermolecular Minisci alkylation reaction on a compound shown as a formula I, a compound shown as a formula II and an acid under a visible light irradiation condition to generate a compound, modified by a histidine residue imidazole ring in polypeptide or protein, shown as a formula III. According to the method, high-selectivity post-transcriptional modification (PTM) onC-2 site of a histidine residue imidazole ring is realized for the first time, a modification means of non-natural amino acids in polypeptide and protein is simplified, the limitation of incompatibility of amino acids and functional groups in traditional polypeptide and protein modification is overcome, and a new means for post-transcriptional modification of polypeptide or protein is broadened. The invention provides an efficient and brand-new method for establishing a new drug molecular library and screening high-throughput active drugs for protein and polypeptide drugs 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 Applications(China)
IPC IPC(8): C07K14/00C07K7/06C07K1/02
CPCC07K14/00C07K7/06
Inventor 王平陈小平叶发荣
Owner SHANGHAI JIAO TONG UNIV
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