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Stable polypeptide used for resisting estrogenic receptor alpha and application thereof

A technology of fluorescein and fluorescein isothiocyanate, which is applied in the direction of peptides, antineoplastic drugs, peptide/protein components, etc., can solve problems such as poor effects, and achieve significant technological progress, high resistance to degradation, and stable helicity Effect

Inactive Publication Date: 2018-05-29
PEKING UNIV SHENZHEN GRADUATE SCHOOL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] Aiming at the above-mentioned technical problems in the prior art, the present invention provides a stable polypeptide for resisting estrogen receptor α and its use, the stable polypeptide for resisting estrogen receptor α and its use To solve the technical problem of poor efficacy of drugs for the treatment of estrogen receptor alpha-positive breast cancer in the prior art

Method used

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  • Stable polypeptide used for resisting estrogenic receptor alpha and application thereof
  • Stable polypeptide used for resisting estrogenic receptor alpha and application thereof
  • Stable polypeptide used for resisting estrogenic receptor alpha and application thereof

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Effect test

Embodiment 1

[0099] In one embodiment of the invention, stabilized polypeptides based on non-natural aspartic acid to form amide bond closures are able to cross cell membranes.

[0100] The present invention is based on the sequence HKILHRLLQ on the coactivator that interacts with estrogen receptor α, and uses the polypeptide solid-phase synthesis method to synthesize the polypeptide. The linear polypeptide is named as polypeptide 1. At the same time, the i-position lysine and i+3-position histidine sites that do not participate in the interaction are mutated into amino acids with side chain carboxyl groups (here, take unnatural aspartic acid as an example) and amino acids with side chain amino groups (Here, diaminopropionic acid is taken as an example), the polypeptide is synthesized in solid phase, the crude polypeptide is cut from the solid phase resin with trifluoroacetic acid, and the target polypeptide is purified by high performance liquid chromatography, and the polypeptide is ident...

Embodiment 2

[0107] In order to further understand the present invention, research polypeptide 2 (sequence is H-Arg-cyclo(isoAsp-Ile-Leu-Dap)-Arg-Leu-Leu-Gln-NH 2 ) interacting with the estrogen receptor ERα, and the crystal structure of the complex was resolved. First, a stable polypeptide was synthesized by solid-phase synthesis, and the protein ERα-LBD was purified and separated. The SDS-PAGE electrophoresis and gel chromatography chromatograms of the protein are shown in figure 1 . Then, 2 to 4 times the polypeptide was incubated with ERα-LBD, concentrated to about 4 mg / ml, and then crystals of the complex were obtained by the sessile drop method ( figure 2 ), and then collected multiple sets of X-ray diffraction data, and determined the phase with the molecular replacement method, corrected the structural model with the COOT software, and optimized the structure with the Phenix software, and finally obtained the crystal structure of the protein-stabilized polypeptide complex.

Embodiment 3

[0109] Crystal structure analysis of the complex of ERα ligand-binding domain and polypeptide 2, see image 3 , it can be seen from the crystal structure diagram that the hydrophobic leucine residue of the stabilizing polypeptide is just inserted into the hydrophobic pocket bound by the coactivator of the ligand binding domain of ERα. The 542-position negatively charged amino acid glutamic acid (Glu) on the surface of the estrogen receptor ERα and the 362-position positively charged amino acid lysine (Lys) form a "charged clamp" structure to further stabilize the binding of the polypeptide by forming an ionic bond with the main chain of the polypeptide. Isoleucine at position 3 and leucine at position 4 can form a hydrogen bond with glutamic acid at position 542 of the ERα ligand binding domain; lysine at position 362 of the ligand binding domain of ERα can form a hydrogen bond with the 7 Leucine at position 8 forms a hydrogen bond, further stabilizing the interaction. The st...

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Abstract

The invention provides a polypeptide of which the structure is disclosed in the description. The invention also provides application of the polypeptide for preparing a medicine capable of inhibiting the growth activity of positive cancer cells of estrogenic receptors. The invention develops one category of stable polypeptide estrogenic receptor antagonist which has relatively good stability and can penetrate through a cytomembrane. The antagonist can be combined with the activated estrogenic receptor alpha to inhibit the transcription activity of the estrogenic receptor alpha, relatively goodbiological activity is displayed, and the growth of the positive cancer of the estrogenic receptor is inhibited. Furthermore, the estrogenic receptor alpha is combined with a clinical medicine-tamoxifen to display better anti-cancer activity better than the anti-cancer activity obtained when medicines are singly used.

Description

Technical field: [0001] The invention belongs to the field of bioengineering and relates to a polypeptide, in particular to a stable polypeptide for resisting estrogen receptor α and its application. Background technique: [0002] Breast cancer is one of the major gynecological malignancies that endanger the health and lives of women worldwide, and its morbidity and mortality rank first among female malignancies. [0003] More than 70% of breast cancers are estrogen receptor alpha (ERα)-positive breast cancers, a transcription factor whose overactivation activates the expression of some oncogenes that drive ER-positive cancer cells growth. [0004] Some small molecule inhibitors have been developed for the tumor target of ERα. For example, tamoxifen (tamoxifen) is currently the most widely used endocrine therapy drug for breast cancer. The ligand binds to the pocket and inhibits its activity, thereby inhibiting the growth of tumor cells. However, the ensuing drug resistan...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K7/08A61K38/08A61K38/10A61P35/00A61K31/138
CPCA61K31/138A61K38/00C07K7/06C07K7/08A61K2300/00
Inventor 谢名胜李子刚
Owner PEKING UNIV SHENZHEN GRADUATE SCHOOL
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