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High-activity tumor inhibitor as well as preparation method and application thereof

A kind of function, amino acid technology, applied in the field of tumor treatment, can solve the problem of unsatisfactory curative effect and achieve the effect of tumor inhibition

Inactive Publication Date: 2017-04-26
BAO KANG BIOMEDICAL HEALTHCARE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In recent years, although a variety of tumor treatment drugs and methods have been developed, the curative effect on malignant tumors such as liver cancer is not satisfactory.

Method used

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  • High-activity tumor inhibitor as well as preparation method and application thereof
  • High-activity tumor inhibitor as well as preparation method and application thereof
  • High-activity tumor inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0220] Example 1 Screening of YAP inhibitory polypeptides

[0221] 1.1 The present inventors constructed different phage polypeptide libraries by using YAP protein arrays. Through multiple screening tests, candidate polypeptides capable of blocking YAP-TEAD binding are selected. Then screen out the inhibitory polypeptides that can effectively penetrate cells, reduce the activity of TEAD and down-regulate other YAP target genes from many candidate polypeptides. Test-tube test and PTDX animal experimental model were carried out on the YAP inhibitory polypeptide obtained through screening to confirm, and finally a successful YAP inhibitory polypeptide with curative effect was obtained.

[0222] The findings reveal that YAP (AA50-171) interacts around the globular structure of TEAD1 (AA194-411) and forms extensive interactions through three highly conserved protein interfaces. Interface 1 is the antiparallel β-sheet structure of YAPβ1 (AA53-58) and TEADβ7. Interface 2 is the mu...

Embodiment 2

[0234] Example 2 Modification of YAP inhibitory polypeptide

[0235] Although the polypeptide shown in SEQ ID NO.:1 can bind to TEAD in vitro, further analysis found that it is difficult to be effectively taken up by cells and has low stability.

[0236] In this embodiment, the sequence is modified based on SEQ ID NO.:1. Some of the identified beneficial modifications include: increased intra-peptide disulfide bonds, increased cell penetrating elements.

[0237] The test results are shown in Table 2.

[0238] Table 2

[0239]

[0240] *Stability is the measured plasma stability, the percentage of peptide remaining at the time measured.

[0241] The results show that the plasma stability of the polypeptide shown in SEQ ID NO.:1 after adding a disulfide bond is significantly improved; 34), the proportion of polypeptides capable of penetrating cells increased from less than 10% to 100% (the penetration rate of polypeptides added with RRMKWKK was 100%) and 135%.

Embodiment 3

[0242] Example 3 Modification of YAP inhibitory polypeptide

[0243] Transformation based on the polypeptide of SEQ ID NO.:1:

[0244] a. A disulfide bond is added in the peptide of SEQ ID NO.:1, and the modified sequence is shown in SEQ ID NO.:2;

[0245] b. Based on the sequence shown in SEQ ID NO.:2, X 4 Respectively replaced by Orn or Dab, the transformed sequence is shown in SEQ ID NO.:5 or 6.

[0246] IC for TEAD binding of engineered YAP inhibitory polypeptides in a and b 50 Value and the mensuration of blood plasma stability, test result is as shown in table 3:

[0247] table 3

[0248]

[0249]

[0250] The results showed that the plasma stability of the polypeptide added with disulfide bonds was significantly improved, and the stability was even better after further modification of the polypeptide. And the IC of all modified peptides 50 All values ​​are in the nanomolar range.

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Abstract

The invention provides a high-activity tumor inhibitor as well as a preparation method and an application thereof. To be specific, a key binding site of YAP protein and TEAD is obtained, polypeptides with the best YAP inhibition activity are screened out and modified, for example, amino acid is subjected to substitution, deletion and / or addition (for example, addition of cell penetration segments) by adding disulfide bonds, and a series of polypeptides having a YAP protein activity inhibition effect and good stability are final screened out. Experiments indicate that the polypeptides can effectively inhibit the binding activity of YAP protein with TEAD, thereby having a good treatment effect on gastrointestinal tumors, particularly liver cancers.

Description

technical field [0001] The invention relates to the field of tumor treatment, in particular to a novel YAP protein inhibitory polypeptide for treating digestive tract tumors. Background technique [0002] Liver cancer is one of the most common types of cancer in the world, especially in China. Due to the high incidence of viral hepatitis, the main prognosis of chronic viral hepatitis will be liver cirrhosis and even liver cancer. The current medical level has not mastered any technology and method to cure liver cancer. The main treatment method is local tumor resection by surgery, and very few can undergo liver resection and liver transplantation. Since there is no way to completely remove potential lesions, the recurrence rate of liver cancer after surgery is extremely high. According to statistics, the recurrence rate within 3 years is about 40%, and it exceeds 90% within 7 years. [0003] In recent years, although various tumor treatment drugs and methods have been devel...

Claims

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Application Information

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IPC IPC(8): C07K7/08C07K14/00C07K1/107A61K38/10A61K38/16A61P35/00
Inventor 李康善
Owner BAO KANG BIOMEDICAL HEALTHCARE
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