Polypeptide drug conjugate as well as preparation method and application thereof

A technology for solid-phase synthesis of drug conjugates and peptides, applied in peptide preparation methods, drug combinations, and pharmaceutical formulations, can solve problems such as high bleeding tendency and large ischemic risk, and achieve low cost and good targeting Function, efficient effect

Active Publication Date: 2018-08-24
THE NAT CENT FOR NANOSCI & TECH NCNST OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, since the current oral antiplatelet agents have a greater ischemic risk and a higher bleeding tendency, it is imperative to find new therapeutic drugs that can reduce the occurrence of ischemic events and the risk of bleeding

Method used

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  • Polypeptide drug conjugate as well as preparation method and application thereof
  • Polypeptide drug conjugate as well as preparation method and application thereof
  • Polypeptide drug conjugate as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] In this example, the polypeptide drug conjugate is prepared by the following method, which specifically includes the following steps:

[0070] (1) Weigh 0.3 g of 2-chlorotrityl chloride resin with a degree of substitution of 0.5 mmol / g, put the resin into a reaction tube, add DCM (15 mL / g), and shake for 10 min.

[0071] (2) Filter the resin solution obtained in step (1) through a sand core to remove the solvent, add 0.037g of Fmoc-Ala-OH, then add 0.08g of DIEA, add a small amount of DCM to dissolve, shake for 2h. Then directly add methanol (about 1 mL) to react for 15 minutes to seal the head, and finally wash with DMF and DCM 6 times alternately.

[0072] (3) Add 15 ml of 20% piperidine DMF solution (15 mL / g) to the resin to which the Ala amino acid has been linked in step (2) for 20 min.

[0073] (4) Remove the piperidine solution from the resin treated in step (3), take more than a dozen resins, wash them three times with ethanol, add ninhydrin, KCN, and phenol so...

Embodiment 2

[0085]In this embodiment, the polypeptide drug conjugate is purified by the following method, which specifically includes the following steps:

[0086] (1) Take the crude peptide drug conjugate and put it into a vessel. Dissolve with 2-5 mL of 50% acetonitrile in water.

[0087] (2) Filter the solution in step (1) with a 0.45 μm filter membrane.

[0088] (3) Analysis: 3 μL was used to analyze the crude product by analytical grade HPLC. The mobile phase is water and acetonitrile, the time is 30min, gradient elution, first equilibrate the HPLC with the initial gradient for 5min and then inject the sample, the initial gradient is 95% water, 5% acetonitrile, the end ratio is 5% water, acetonitrile 95%, determine the target Product peak position.

[0089] (4) Preparation: Prepare the dissolved sample for injection. The preparative HPLC was equilibrated for 10 minutes, the initial gradient was 95% water, 5% acetonitrile, the end gradient was 25% water, 75% acetonitrile, and the ...

Embodiment 3

[0092] In this example, the antiplatelet activity of the polypeptide drug conjugate was investigated by using the method that affects the platelet aggregation rate, the method is as follows:

[0093] (1) Weigh 1 mg of the prepared polypeptide drug conjugate, add 1 mL of ethanol to prepare a 1 mg / mL drug solution; calculate the equivalent concentration of ticagrelor dosage according to the molecular weight of the conjugate and ticagrelor, and weigh the Cagrel powder 0.42mg, add 1mL ethanol and fully dissolve.

[0094] (2) Dilute the conjugate and ticagrelor solution in step (1) 6 times according to the ratio of 1:2, that is, the corresponding conjugate drug concentration is 0.5mg / mL, 0.25mg / mL, 0.125mg / mL, 0.0625mg / mL, 0.03125mg / mL, 0.015625mg / mL, reserve.

[0095] (3) Take 20ml of porcine venous blood, anticoagulate it with 3.8% sodium citrate 9:1, and collect it in a plastic centrifuge tube. Thoroughly mix blood and anticoagulant. Centrifuge at 200g for 10min at room temp...

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Abstract

The invention provides a polypeptide drug conjugate as well as a preparation method and application thereof. The polypeptide drug conjugate is prepared from ticagrelor and CREKA polypeptide, wherein the ticagrelor is connected with the CREKA polypeptide. Compared with the existing platelet inhibitor, the polypeptide drug conjugate provided by the invention not only can achieve high concentration enrichment of tumor tissue sites, but also realizes high concentration enrichment in atherosclerosis tissues by connecting the ticagrelor with the polypeptide, so that the platelet function in specificareas is inhibited without affecting platelet function during normal blood circulation, the bleeding risk of the conventional platelet inhibitor is reduced while the drug availability is improved, and better and safer tumor metastasis inhibition or acute coronary syndrome prevention function is accordingly realized.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a polypeptide drug conjugate and its preparation method and application. Background technique [0002] Malignant tumor is one of the main diseases that threaten human life and health at present, and its infiltration and metastasis are the characteristic signs of its malignancy. Metastasis of tumor cells through the blood is the main way for distant metastasis of tumors, and it is also the main factor of treatment failure and death of most cancer patients in clinical practice. [0003] The process of tumor metastasis consists of three main steps: tumor cells crossing the vascular endothelial cells of the tumor tissue, moving out from the primary site into the blood circulation system, tumor cells running with the blood, and tumor cells implanting at the metastatic site. The process of metastasis involves a variety of cells Adhesion molecules, extracellular matrix, and other inter...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/64A61K31/519C07K7/06C07K1/04A61P9/10A61P35/04A61P7/02
CPCA61K31/519A61K47/64A61P7/02A61P9/10A61P35/04C07K7/06
Inventor 聂广军史权威李素萍张银龙
Owner THE NAT CENT FOR NANOSCI & TECH NCNST OF CHINA
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