Signal transducer and activator of transcription 3 (STAT3) inhibitory polypeptide and preparation method and application thereof

A technology for inhibiting polypeptide and microwave reactions, which is applied in the field of antitumor drugs, can solve the problems of high negative charge requirements, large area of ​​action, and difficulty in making drugs, and achieve the effects of improving efficiency, promoting apoptosis, and increasing the rate of coupling reactions

Active Publication Date: 2021-03-19
WUXI PEOPLES HOSPITAL
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, since STAT3 dimerization is a protein-protein interaction with a large area of ​​action, it is difficult to block the interaction with small molecular compounds or short peptides. At the same time, the related domains and positively charged residues gather, The negative charge carried by the compound is highly demanding, and it is not easy to be drugged. Various restrictions make the development of STAT3 inhibitors difficult, and most compounds are in the preclinical research stage

Method used

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  • Signal transducer and activator of transcription 3 (STAT3) inhibitory polypeptide and preparation method and application thereof
  • Signal transducer and activator of transcription 3 (STAT3) inhibitory polypeptide and preparation method and application thereof
  • Signal transducer and activator of transcription 3 (STAT3) inhibitory polypeptide and preparation method and application thereof

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preparation example Construction

[0030] The present invention also provides a method for preparing the above-mentioned inhibitory polypeptide, which includes the following steps: (1) after sequentially using DCM and NMP to swell the resin, clean the swollen resin;

[0031] (2) Mix the swollen resin with the piperidine / NMP solution containing 0.1M HOBT, react in the first microwave for 1 min, filter the solution after cooling, then mix it with the piperidine / NMP solution containing 0.1M HOBT, and mix it with the piperidine / NMP solution containing 0.1M HOBT for the second Microwave reaction 4min, get off the resin of the Fmoc protecting group of initial connection after cooling; The power of the first microwave is 15W; The power of the second microwave is 25W;

[0032] (3) Mix the accelerator liquid with the resin that removes the Fmoc protecting group that is initially connected, react with the third microwave for 7 minutes, filter the reaction liquid after cooling, and wash the resin to obtain Fmoc-Leu-Rink am...

Embodiment 1

[0046] Pro-Phe-Ser-Ser-Val-Pro-Glu-Ile-Val-His-His-Tyr-Ala-Ser-Arg-Lys-Leu-Pro-Ile-Lys-Gly-Ala-Glu-His-Met- Microwave-promoted solid-phase synthesis of Ser-Leu-Leu-Tyr-Pro-Val-Ala-Ile-Arg-OH (SEQ ID NO.1-OH)

[0047] (1) Swelling of the resin

[0048] Weigh 50 mg of Fmoc-Wang amide-MBHA Resin (substitution amount 0.4 mmol / g), swell with 7 mL of DCM for 30 min, filter to remove DCM, then swell with 10 mL of NMP for 30 min, and finally rinse with NMP, DCM, and 7 mL of NMP respectively.

[0049] (2) Microwave promotes removal of Fmoc protecting group

[0050] Put the swollen resin into the reactor, add 7mL of 25% piperidine / NMP (V / V) solution containing 0.1M HOBT, react in the microwave reactor for 1min, the microwave power is 15W, and the reaction temperature is controlled at 50°C Within the time period, use an air compressor to compress the air to cool, and filter the solution after the reaction; add 7 mL of 25% piperidine / NMP (V / V) solution containing 0.1M HOBT and react in ...

Embodiment 2

[0064] Pal-Pro-Phe-Ser-Ser-Val-Pro-Glu-Ile-Val-His-His-Tyr-Ala-Ser-Arg-Lys-Leu-Pro-Ile-Lys-Gly-Ala-Glu-His- Met-Ser-Leu-Leu-Tyr-Pro-Val-Ala-Ile-Arg-NH 2 (Pal-SEQ ID NO.1-OH, wherein Pal is palmitic acid) microwave-facilitated solid-phase synthesis

[0065] According to the method provided in Example 1, the inhibitory polypeptides of the above sequences were synthesized according to the corresponding sequences, and their respective molecular weights were confirmed by electrospray mass spectrometry (ESI-MS). The theoretical relative molecular mass is 4081.9. ESI-MS m / z:found[M+4H] 4+ 1021.4, [M+5H] 5+ 817.3;calu[M+4H] 4+ 1020.8, [M+5H] 5+ 816.8.

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Abstract

The invention provides signal transducer and activator of transcription 3 (STAT3) inhibitory polypeptide and a preparation method and application thereof, and relates to the technical field of antitumor drugs. The inhibitory polypeptide has an amino acid sequence shown as SEQ ID NO.1, can be combined with highly expressed STAT3 in tumor cells, and promotes tumor cell apoptosis and inhibits proliferation and migration by preventing STAT3 dimerization; meanwhile, toxicity to normal cells is low, and excellent selectivity is achieved. The inhibitory polypeptide is efficiently and quickly synthesized by adopting amicrowave-promoted Fmoc / tBu orthogonal protection solid-phase synthesis strategy, thus the polypeptide synthesis efficiency is greatly improved, and the synthesis period is shortened;and moreover, the purity of a crude product of the novel STAT3 inhibitory polypeptide prepared by microwave-promoted solid-phase synthesis is greater than 80%, and industrial production is facilitated, so that the STAT3 inhibitory polypeptide and the pharmaceutically acceptable salt thereof can be potentially applied to anti-tumor clinical treatment, and have a wide development prospect.

Description

technical field [0001] The invention belongs to the technical field of antineoplastic drugs, and in particular relates to a STAT3 inhibitory polypeptide and its preparation method and application. Background technique [0002] As a common and frequently-occurring disease that seriously threatens human health, malignant tumor has become the second largest disease in the world after cardiovascular disease in terms of mortality. Chemotherapy, as a systemic tumor treatment, has become the main strategy of tumor treatment. In recent years, with the development of tumor biology and related disciplines, tyrosine kinase receptor monoclonal antibody Trastuzumab, multi-target new drug Sunitinib, and epidermal growth factor receptor inhibitor Gifitinib have been developed for key factors in tumor signal transduction pathways. Molecular targeted drugs have been successfully applied clinically, and cancer chemotherapy has entered a new era. Although these early tumor molecular targetin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/00C07K1/08C07K1/06C07K1/04C07K1/20A61K38/16A61P35/00
CPCC07K14/001A61P35/00A61K38/00Y02P20/55
Inventor 邹健张博邵珺汪京京纪丽殷莹
Owner WUXI PEOPLES HOSPITAL
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