Cyclic peptide compound as well as preparation method and application thereof

A technology of compound and cyclic peptide, which is applied in the field of cyclic peptide compound and its preparation, can solve the problems of binding and breaking, and achieve the effect of rapid response and fast response speed

Pending Publication Date: 2022-03-29
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It utilizes OPA and Cys's mercapto group and Lys's amino group to form an isoindole sulfide structure, but this structure will decompose under the conditions of light and oxygen, so that the binding will be broken

Method used

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  • Cyclic peptide compound as well as preparation method and application thereof
  • Cyclic peptide compound as well as preparation method and application thereof
  • Cyclic peptide compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] Determining the structure by taking Lys's own OPA cyclization as an example

[0091]

[0092] Lys (1.0equiv, 0.02mmol, 2.9mg) was dissolved in 2mL of PBS buffer (pH=8.0) and 2mL of MeOH at room temperature, and then 2.68mg (1.0equiv) of o-phthalaldehyde (OPA) was weighed and added to the solution, After stirring at room temperature for 5 min, the product of Lys self-cyclization was obtained. Purification and isolation were carried out by HPLC. Lys self-cyclization product 1 H-NMR, 13 C-NMR, DEPT-135, HSQC and NOESY spectra are listed in figure 1 .

[0093] 1 H NMR (600MHz, DMSO-d 6 )δ7.94(d,J=7.8Hz,1H),7.77-7.70(m,2H),7.63-7.60(m,1H),5.09–4.88(m,2H),4.51–4.40(m,2H) ,3.77–3.68(m,1H),2.35-2.26(m,1H),2.08-1.98(m,1H),1.94-1.85(m,1H),1.75-1.59(m,2H),1.49-1.38( m,1H). 13 C NMR (150MHz, DMSO-d 6 )δ 170.3, 157.8, 141.2, 132.9, 129.2, 128.6, 123.3, 121.6, 58.8, 55.1, 45.7, 34.2, 28.6, 21.7.

Embodiment 2-15

[0095] Taking Linear Peptide S2 as an Example to Introduce the Head-Side Chain Cyclization Process

[0096]

[0097] Condition [A]: Weigh the linear peptide (S2) (TFA salt, 0.02 mmol, 13.1 mg) into an 8 mL reaction vial, add 2 mL of PBS buffer (pH=8.0) and 2 mL of MeOH to completely dissolve the linear peptide. Subsequently, 2.68 mg (1.0 equiv) of o-phthalaldehyde was weighed and added into the solution, stirred for 5 min, and purified by HPLC to obtain a cyclization product.

[0098] Condition [B]: Weigh the linear peptide (S2) (TFA salt, 0.02mmol, 13.1mg) into an 8mL reaction vial, add 2mL H 2 O and 2 mL of MeOH were used to completely dissolve the linear peptide, followed by the addition of 3 equiv DIPEA to neutralize the TFA of the linear peptide. Subsequently, 2.68 mg (1.0 equiv) of o-phthalaldehyde was weighed and added into the solution, stirred for 5 min, and purified by HPLC to obtain a cyclization product.

[0099] Condition [C]: Weigh the linear peptide (S2) (T...

Embodiment 2

[0109] The impact of reaction concentration on reaction time in embodiment 2

[0110] Weigh the linear peptide S2 (TFA salt, 0.02mmol, 13.1mg) into an 8mL reaction bottle, add 2mL PBS buffer (pH=8.0) and 2mL MeOH to completely dissolve the linear peptide, and prepare a solution with a concentration of 5mM. Then weigh 2.68 mg (1.0 equiv) of o-phthalaldehyde (OPA) and add it into the solution. After stirring for 10 s, take out 50 ul of the reaction system and put it into a 1.5 ml EP tube, and add 5 ul of HCOOH to quench the reaction system. Monitored by LC-MS, the raw material can be completely reacted within 10s.

[0111] Similarly, the linear peptide S2 was reacted at a concentration of 50uM, and the raw material could be completely reacted within 2 minutes. Therefore, it can be explained that the reaction is very rapid, and the lower the reaction concentration, the longer the required reaction time.

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PUM

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Abstract

The invention provides a cyclic peptide compound as well as a preparation method and application thereof. According to the invention, an aromatic ring precursor with diformaldehyde is used as a linker, under mild conditions, two amino groups on an unprotected peptide chain are rapidly and efficiently subjected to ring-forming labeling in a head-side chain mode and a side chain-side chain mode, and the formed isoindoline imine has a relatively stable structure and can be used for preparing the isoindoline imine. And meanwhile, an electron-deficient electrophilic reagent can be used for subsequent modification to obtain a more complex structure. The use amount of required samples is small, the reaction system is clean, and the product structure is stable; and the method is suitable for cyclization reactions of all peptide chains containing two aminopeptides except cysteine. According to the invention, very favorable support is provided for subsequent construction of a cyclic peptide molecular library and high-throughput drug screening.

Description

technical field [0001] The invention belongs to the field of polypeptide chemical synthesis, and in particular relates to a cyclic peptide compound and its preparation method and application. Background technique [0002] Protein-protein interaction (PPI) plays a very important role in the life activities of organisms. Most protein-protein interactions (PPIs) occur between short peptides and globular proteins; peptides involved in surface interactions play an important role, and the use of peptide modification to interfere with protein-protein interactions has great application prospects. Compared with linear peptides, cyclic peptide compounds show stronger rigidity, while having higher enzymatic stability, membrane permeability, and higher oral availability. Currently, many strategies for constructing cyclic peptides have been developed, such as Cu-catalyzed alkynyl [3+2] cycloaddition, Ru-catalyzed olefin metathesis, Pd-catalyzed cysteine ​​Cys-SH and lysine Lys- NH 2 a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/56C07K14/00C07K5/02C07K1/02
CPCC07K7/56C07K14/00C07K5/02C07K1/02
Inventor 陈弓李博王岚陈祥祥何刚
Owner NANKAI UNIV
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