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Long-acting thymosin alpha1-polyethylene glycol modifiers

A modification and compound technology, which is applied in the field of long-acting thymosin α1 pegylated modification, can solve the problems of frequent injections, large dosage, and high price

Inactive Publication Date: 2010-06-30
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Currently clinically used Tα1 is a chemical synthetic product, sterilized dry powder preparation, the clinical dosage for the treatment of chronic hepatitis B is 1.6mg / time, injected 2 times / week, 6 months / course of treatment, with large dosage and frequent injections and expensive disadvantages

Method used

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  • Long-acting thymosin alpha1-polyethylene glycol modifiers
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  • Long-acting thymosin alpha1-polyethylene glycol modifiers

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0170] Example 1: Ac-[Cys 5 (mPEG 5000 -MAL)] Tα1 (BTJB005)

[0171] 1.1Ac-[Cys 5 ] Synthesis of Tα1:

[0172] Synthesized by solid-phase method [Cys 5 ]Tα1: Wang resin 100mg is the solid phase carrier, Fmoc-AA-OH (1-10 times the amount) is the raw material, DCC (1-10 times the amount), HOBt (1-10 times the amount) is the condensation agent, divided by Cys 5 Replace Val 5 In addition, the remaining amino acid residues are synthesized according to the Tα1 sequence to obtain Ac-[Cys 5 ] Fully protected peptide resin of Tα1. After drying, TFA was cracked, reacted at room temperature for 20-200 minutes, filtered off the resin, added diethyl ether to precipitate a white solid, dissolved in water, and lyophilized to obtain 161 mg of a white solid. RP-HPLC purification, ESI-MS identification, [M] 2+ Peak: 1551.0 (theoretical: 3098).

[0173] 1.2Ac-[Cys 5 (mPEG 5000 Synthesis of -MAL)]Tα1

[0174] Purified Ac-[Cys 5 ] Tα1 is dissolved in water, adjust the pH range of 5-10...

Embodiment 2

[0176] Example 2: Ac-[Cys 8 (mPEG 5000 -MAL)] Tα1 (BMJBO08)

[0177] Synthesize Ac-[Cys according to embodiment 1.1 method 8 ] Tα1 to obtain 116 mg of crude peptide. RP-HPLC purification, ESI-MS identification, [M] 2+ Peak: 1543.0 (theoretical: 3083).

[0178] Synthesize Ac-[Cys according to the method of embodiment 1.2 8 (mPEG 5000 -MAL)]Tα1, the product was separated by HPLC and lyophilized to obtain 16.9 mg of white solid, with a yield of 37.1%.

[0179] Ac-[Cys 8 (mPEG 5000 -MAL)]Tα1 was identified by MALDI-TOF-MS, and there were a series of peaks around 8247, and the molecular weight difference between the two adjacent peaks was about 44, which had the typical structural characteristics of polyethylene glycol.

Embodiment 3

[0180] Example 3: Ac-[Cys 11 (mPEG 5000 -MAL)] Tα1 (BMJB011)

[0181] Synthesize Ac-[Cys according to embodiment 1.1 method 11 ] Tα1 to obtain 143 mg of crude peptide. RP-HPLC purification, ESI-MS identification, [M] 3+ Peak: 1034.9 (theoretical: 3098).

[0182] Synthesize Ac-[Cys according to the method of embodiment 1.2 11 (mPEG 5000 -MAL)]Tα1, the product was separated by HPLC and lyophilized to obtain 21.4 mg of white solid, with a yield of 28.9%.

[0183] Ac-[Cys 11 (mPEG 5000-MAL)]Tα1 was identified by MALDI-TOF-MS, and there were a series of peaks around 8282, and the molecular weight difference between the two adjacent peaks was about 44, which had the typical structural characteristics of polyethylene glycol.

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Abstract

The invention relates to long-acting thymosin alpha1-polyethylene glycol modifiers(T alpha1-PEGs) and a preparation method thereof, a pharmaceutical composition containing the same and applications to treating or preventing diseases related to immunodeficiency, immunologic hypofunction, and the like. The long-acting thymosin alpha1-polyethylene glycol modifiers(T alpha1-PEGs) are applied to treating or preventing diseases related to hepatitis B, hepatitis C, liver cancer, malignant melanoma, non-small cell lung cancer, and SARS, AIDS, and the like which are caused by coronavirus.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 2005 10117752.7 submitted on November 10, 2005. field of invention [0002] The present invention relates to thymosin α1 pegylated modification (Tα1-PEG s), a preparation method of Tα1-PEGs, a pharmaceutical composition containing them, and a separate method for treating or preventing diseases related to immunodeficiency and immunodeficiency The use of medicine or combination medicine, including the treatment of hepatitis B, hepatitis C, liver cancer, malignant melanoma, non-small cell lung cancer, SARS (severe acute respiratory syndrome) caused by coronavirus, AIDS and other related diseases or application in prevention. Background technique [0003] Thymosin α1 (Thymosin alpha 1, Tα1) is one of the active polypeptides secreted by the thymus, which has a high sequence conservation, and Tα1 from different species has the same chemical structure. Tα1 consists of 28 amino acid residues, its ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K17/08A61K47/48A61K38/22A61P31/20A61P31/14A61P31/18A61P35/00A61K47/60
Inventor 刘克良郄建坤马金波郑建全董泗建周文霞齐春会
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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