Sulfonium salt-based stable HDAC-targeting polypeptide drug conjugate and application thereof

A conjugated and stable technology, applied in the field of bioengineering, can solve the problems of poor biosafety, multiple toxic and side effects, and achieve the effect of good biosafety, good biocompatibility, and increased therapeutic window.

Active Publication Date: 2022-03-08
XIEHE HOSPITAL ATTACHED TO TONGJI MEDICAL COLLEGE HUAZHONG SCI & TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although HDAC inhibitors and apoptotic polypeptides can be used in the treatment of various tumors, they each have some disadvantages. For example, HDAC inhibitors have more toxic and side effects in clinical applications. It has strong hydrophobicity, which makes it inhibit the proliferation of both normal cells and tumor cells, so the biological safety is poor

Method used

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  • Sulfonium salt-based stable HDAC-targeting polypeptide drug conjugate and application thereof
  • Sulfonium salt-based stable HDAC-targeting polypeptide drug conjugate and application thereof
  • Sulfonium salt-based stable HDAC-targeting polypeptide drug conjugate and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1: Design of HDAC-targeted polypeptide drug conjugates

[0024] The present invention adopts the method of coupling HDAC inhibitors with sulfonium salt-stabilized apoptosis polypeptides to design HDAC-targeted polypeptide drug conjugates, such as figure 1 As shown, we selected the previously reported apoptotic polypeptide as the entry point (the original apoptotic polypeptide sequence: RLLRLLRLRRLRL, R is arginine, L is leucine), and the polypeptide was stabilized using the sulfonium salt-stabilized peptide methodology. Try to improve the stability of the peptide, and rely on the hydrophilicity of the sulfonium salt to change the hydrophilicity and hydrophobicity of the overall apoptosis peptide, and try to reduce the toxicity to normal cells. In order to further improve the anti-tumor activity of the polypeptide, we introduced the carbon-terminus of the polypeptide into the HDAC inhibitor hydroxamic acid structure, which has a broad spectrum of inhibitory activ...

Embodiment 2

[0026] Example 2: Synthesis and preparation of stable peptide drug conjugates targeting HDAC

[0027] (1) Resin swelling and deprotection:

[0028] The specific operation of solid-phase peptide synthesis is as follows: figure 2As shown in the roadmap: The special 2-Chlorotityl-N-Fmoc-hydroxylamine resin (loading degree: 0.54mmol / g) is used for the solid-phase synthesis of polypeptides with hydroxamic acid. The procedure was as follows: 2-Chlorotityl-N-Fmoc-hydroxylamine resin was swollen with DCM for 15 minutes. Use 50% morphine (dissolved in DMF) to remove the Fmoc protecting group for 30 minutes each time, twice in total, and then wash with DMF / DCM alternately for 3 times.

[0029] (2) Synthesis of resin polypeptide:

[0030] The above-mentioned deprotected resin, the prepared (1) Fmoc-6-amino-caproic acid (5eq, 0.4M, DMF) solution, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate ( PyBOP) (5eq, 0.4M, DMF) solution and N,N-diisopropylethylamine (DIPEA) (10eq) ...

Embodiment 3

[0031] Example 3: Enzyme Activity Inhibition Effect of Stable Polypeptide Drug Conjugate Targeting HDAC

[0032] The identification of the inhibitory effect of HDAC enzyme activity was carried out with a commercially purchased HDAC enzyme activity detection kit, and each operation was repeated at least three times. HDAC enzymes came from HeLa nuclear extracts reported in many literatures. The enzyme activity results were based on commercial reagents. The operation of the box is carried out, and finally the inhibitory activity of the peptide drug conjugate on the HDAC protein is measured with a microplate reader, as shown in Table 1:

[0033] Table 1 Different polypeptide drugs designed by the present invention are to HDAC enzyme activity inhibitory effect figure

[0034]

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Abstract

The invention relates to a sulfonium salt stable targeting HDAC polypeptide drug conjugate and application thereof, a sulfonium salt stable apoptosis-promoting polypeptide is coupled with an HDAC inhibitor to form a stable polypeptide HDAC inhibitor with tumor selective toxicity, the nonspecific toxicity of apoptosis polypeptide chemically stabilized by sulfonium salt is remarkably reduced, the stability of protease is higher, and the tumor selective toxicity of the apoptosis polypeptide is remarkably reduced. When a polypeptide drug conjugate is formed by coupling with an HDAC inhibitor, the polypeptide drug can significantly improve the selective toxicity to tumor cells, and has weak toxicity to normal cells. Cell proliferation, cell apoptosis and cell cycle arrest experiments prove that the polypeptide can effectively inhibit proliferation of malignant liver cancer, has relatively good biological safety and has a potential anti-tumor clinical application prospect.

Description

technical field [0001] The invention belongs to the field of bioengineering and relates to a polypeptide drug conjugate, in particular to a sulfonium salt-based HDAC-targeted polypeptide drug conjugate and an application thereof. Background technique [0002] Cancer is a major public health problem worldwide. According to the 2020 global cancer data released by the WHO, there will be 4.57 million new cancer cases and more than 3 million deaths in China in 2020. The number of new cancer cases in China ranks first in the world. Lung cancer, colorectal cancer, liver cancer, gastric cancer, and breast cancer are among the top ten cancers in terms of death toll. The types of tumors and the causes of tumors are different in different genders and ages. The complexity of tumor diseases has brought challenges to human beings to overcome this disease. Traditional tumor treatment methods include surgery, radiotherapy and chemotherapy, but tumor recurrence, metastasis and drug resista...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/64A61K38/10A61K31/16A61P35/00
CPCA61K47/64A61K38/10A61K31/16A61P35/00A61K2300/00
Inventor 王冬园张玉李子刚曾芳黄怡菲杜丽尹丰
Owner XIEHE HOSPITAL ATTACHED TO TONGJI MEDICAL COLLEGE HUAZHONG SCI & TECH UNIV
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