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BRD4 protein targeting anti-tumor polypeptide and application thereof

A technology of targeting and peptide beads, which can be used in anti-tumor drugs, peptides, peptide libraries, etc., and can solve the problems of toxic side effects, poor selectivity, and low specificity.

Active Publication Date: 2021-01-01
SUN YAT SEN UNIV SHENZHEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the existing small molecule inhibitors of BRD4 have a common weakness - they cannot distinguish between BRD4 and its homologous proteins well, the selectivity is poor, and the anticancer activity of the inhibitors needs to be improved
Moreover, small molecule drugs have problems such as poor selectivity and low specificity, are prone to "off-target" effects, and are prone to strong toxic and side effects, which limits the large-scale clinical application of small molecule drugs

Method used

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  • BRD4 protein targeting anti-tumor polypeptide and application thereof
  • BRD4 protein targeting anti-tumor polypeptide and application thereof
  • BRD4 protein targeting anti-tumor polypeptide and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Embodiment 1 targeting BRD4-BD1 domain polypeptide

[0088] Targeting BRD4-BD1 domain polypeptides, the core amino acid sequences are: Ac-KR-K(Ac)-VS, Ac-TG-K(Ac)-WS, Ac-IQ-K(Ac)-RP, Ac - LA-K(Ac)-SF, Ac-DP-K(Ac)-IT and Ac-AD-K(Ac)-DG.

[0089] Table 1 The polypeptide sequence targeting BRD4-BD1 domain

[0090] Peptide number amino acid sequence of polypeptide B1-1 Ac-KR-K(Ac)-VS (SEQ ID NO.: 1) B1-2 Ac-TG-K(Ac)-WS (SEQ ID NO.:2) B1-5 Ac-IQ-K(Ac)-RP (SEQ ID NO.: 3) B1-6 Ac-LA-K(Ac)-SF (SEQ ID NO.:4) B1-7 Ac-DP-K(Ac)-IT (SEQ ID NO.:5) B1-8 Ac-AD-K(Ac)-DG (SEQ ID NO.:6)

Embodiment 2

[0091] Embodiment 2 targeting BRD4-BD2 domain polypeptide

[0092] Targeting BRD4-BD2 structure and polypeptide, its core amino acid sequences are: GD-K(Ac)-LY, WR-K(Ac)-PD, IT-K(Ac)-NL, YK-K(Ac)- PY, GV-K(Ac)-SR, RH-K(Ac)-LK.

[0093] The polypeptide contains acetylated lysine K (Ac), and except the third amino acid, the amino acids at other positions are L-type natural amino acids. Concrete operation is with embodiment 1.

[0094] Table 2 The polypeptide sequence targeting the BRD4-BD2 domain

[0095] Peptide number amino acid sequence of polypeptide B2-1 Ac-WR-K(Ac)-PD (SEQ ID NO.7) B2-2 Ac-IT-K(Ac)-NL (SEQ ID NO.8) B2-3 Ac-YK-K(Ac)-PY (SEQ ID NO.9) B2-4 Ac-RH-K(Ac)-LK (SEQ ID NO.10) B2-5 Ac-GD-K(Ac)-LY (SEQ ID NO.11) B2-6 Ac-GV-K(Ac)-SR (SEQ ID NO.12)

Embodiment 3

[0096] Example 3 Screening of acetylated lysine polypeptides

[0097] (1) Synthesis of acetylated lysine peptide library

[0098] The present invention selects 20 kinds of L-type natural amino acids to form a pentapeptide compound library; the compound library is a pentapeptide sequence in which the third amino acid is acetylated lysine, and the amino acids at both ends are arranged and combined with 20 kinds of natural amino acids, expressed as NH 2 -AA 5 -AA 4 -K(Ac)-AA 2 -AA 1 -CONH 2 , up to 20 types of peptide sequences 4 kind. The peptide compound library was synthesized by an automatic peptide synthesizer, and then the amino acids with higher frequency at each site were selected after preliminary screening and mass spectrometry sequencing by COPAS, and the peptide compound library was further constructed. The peptide compound library is screened to obtain and optimize the peptide sequence with higher affinity. The peptide library was synthesized using an automat...

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Abstract

The invention discloses BRD4 protein targeting anti-tumor polypeptide and application thereof, and a microarray screening method has the advantages of small raw material consumption, high flux and small error. The polypeptide targeting the BRD4-BD1 / BRD4-BD2 structural domain based on high-throughput screening has the advantages of high affinity and high selectivity, and the effect of the polypeptide in detection or treatment of cancers. The polypeptide has the characteristics of high affinity and strong specificity. In addition, a high-affinity and high-selectivity polypeptide sequence for screening the BRD4 protein by using a one-bead-one-peptide technology is created for the first time. According to the method, a polypeptide compound library which has no preference and is diverse in variety can be rapidly established, and the defects that a traditional screening method is tedious in steps, low in screening experiment speed and low in efficiency are overcome.

Description

technical field [0001] The invention belongs to the field of biotechnology, and relates to an anti-tumor polypeptide targeting BRD4 (Bromodomain-4) protein and its application, in particular to a high-affinity polypeptide targeting BRD4 protein and its application in anti-cancer and cancer detection. Background technique: [0002] The "reader" of acetylated lysine——Bromodomain protein (BRDs), is a kind of conserved protein domain that can specifically recognize acetylated lysine, and can regulate the expression and function of genes. It is reported that it is closely related to the occurrence and development of various diseases. BRDs have a highly conserved bromoprotein functional domain of approximately 110 amino acids, including four α-helical sheets that form a hydrophobic cavity and recognize acetylated lysine. To date, 61 unique domains of BRDs have been discovered. According to the different functions of each BRDs protein, they can be divided into 8 families, and eac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C40B40/10C40B50/14C07K7/06A61K47/42A61P35/00G01N33/68G01N33/574
CPCC40B40/10C40B50/14C07K7/06A61K47/42A61P35/00G01N33/68G01N33/57484G01N33/57423G01N33/57438
Inventor 高理钱李少云张达石子寒杨芬肖奇才周士哲吕婉婷李晗玥
Owner SUN YAT SEN UNIV SHENZHEN
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