Means and methods of enhancing delivery to biological systems

A guanidine group and carboxyl group technology, which can be applied in the directions of urinary system diseases, endocrine system diseases, nano-drugs, etc., can solve the problems of failure to provide, achieve economical production, and avoid allergic or immunogenic effects.

Inactive Publication Date: 2009-10-14
保罗博蒂
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, the prior art fails to provide simple, reversible and non-immunogenic means for enhancing the ability of proteins, nucleic acids, liposomes or micelles (micelles) to cross membrane property barriers in the human or animal body

Method used

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  • Means and methods of enhancing delivery to biological systems
  • Means and methods of enhancing delivery to biological systems
  • Means and methods of enhancing delivery to biological systems

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0168] In the absence of gene fusion (ie, cell penetrating) peptides, SCF (stem Delivery of 20-mer peptide inhibitors of cytokines)

[0169] Target peptide (required for ER export of SCF):

[0170] N-E-E-D-N-E-I-S-M-L-Q-E-K-E-R-E-F-Q-E-V-cooH

[0171] the corresponding arginine-ester-peptide, which is modified according to the invention by esterification of the carboxyl group of glutamic acid with guanidinol;

[0172]

[0173] Gnd = guanidino

[0174] The aspartic acid side chain is protected with a methyl ester: Boc-Asp(OMe)-OH.

[0175] I. Pseudo-arginine-derived SFC derivatives:

[0176] The guanidine group is chemically introduced into the side chain of glutamic acid via an ester bond, separated from the carboxylic acid by a 4-carbon alkyl chain (butyl). The guanidino protecting group is bis-Z(N,N'dibenzyloxycarbonyl).

[0177] Strategy: Boc / Fmoc strategy.

[0178] Precursor used: Fmoc-Glu(ObutylguanidinobisZ(bisZ))-OH.

[0179] Resin: Boc-Val-Pam resin RAPP ...

Embodiment 2

[0191] Synthesis of 1-(2-(benzyloxy)ethyl)-N,N'-di-Boc-guanidine

[0192]49.9 mg (1 mmol, 1 eq.) of NaH were suspended in 10 mL of dry THF under nitrogen. A solution of 298.3 mg (1 mmol, 1 eq.) of 1-(6-hydroxyethyl)-N,N'-di-Boc-guanidine in 10 mL of dry THF was added dropwise over 10 minutes. The solution was stirred at room temperature for 1 hour and 0.12 mL (1 mmol, 1 eq.) of benzyl bromide was added dropwise. The reaction was stirred at room temperature for 2 hours and 30 minutes and checked by TLC. 44.9 mg (1 mmol, 1 eq.) of NaH were added. After 5 hours 30 minutes (total reaction time), TLC indicated little progress and the reaction was allowed to stir overnight. Some water was added and the organic solvent was removed under vacuum. The aqueous phase was extracted three times with ether. Organic phase in anhydrous Na 2 SO 4 Drying and evaporation gave 430.0 mg of a colorless oil. The oil was subjected to flash chromatography on silica (eluent AcOEt:pentane 1:9...

Embodiment 3

[0194] 2-Guanidinoethylbenzoic acid trifluoromethanesulfonate Synthesis of (2-guanidinoethyl benzoate triflate salt)

[0195] 4mL (52mmol, 65eq.) of TFA was added to 315.5mg (0.8mmol, 1eq.) of 1-(2-(benzyloxy)ethyl)-N,N'-di-Boc-guanidine and at room temperature Stir for 3 hours. The solution was evaporated to obtain 336.9 mg (1.1 mmol) of 2-guanidinoethylbenzoic acid triflate as a pale orange oil (yield = 110%).

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Abstract

This invention relates to a peptide or polypeptide (a) which is esterified or thio-esterified (i) at the carboxylate of the C-terminus with a guanidinium alkanol, a guanidinium alkanethiol, a PEG substituted with a guanidinium group and having a free hydroxyl group, or a PEG substituted with a guanidinium group and a sulfhydryl group; (ii) at a side-chain carboxylate of one or more Asp or GIu residues, if present, with a guanidinium alkanol, a guanidinium alkanethiol, a PEG substituted with a guanidinium group and having a free hydroxyl group, or a PEG substituted with a guanidinium group and a sulfhydryl group; (iii) at a hydroxyl group of one or more Ser, Thr or Tyr residues, if present, with a guanidinium alkanoic acid or a PEG substituted with a guanidinium group and a carboxyl group; (iv) at a sulfhydryl group of one or more Cys residues, if present, with a guanidinium alkanoic acid or a PEG substituted with a guanidinium group and a carboxyl group; and / or (v) at the N-terminus with a guanidinium alkanoic acid or a PEG substituted with a guanidinium group and a carboxyl group, wherein said N-terminus is previously amidated with an alpha- or beta-hydroxy acid, and wherein the ester is formed between the hydroxy group of said alpha- or beta-hydroxy acid and the carboxylic group of said guanidinium alkanoic acid or said PEG substituted with a guanidinium group and a carboxyl group; and / or (b) which contains one or more disulfides, the disulfide being formed between the sulfhydryl group of a Cys reside, if present, and a guanidinium alkanethiol or a PEG substituted with a guanidinium group and a sulfhydryl group.

Description

technical field [0001] The present invention relates to a peptide or polypeptide (a) which undergoes esterification or thioesterification as follows: (i) a carboxylate at the C-terminus with guanidinium alkanol, guanidinium alkanol ( guanidinium alkanethiol), PEG substituted by guanidinium group with free hydroxyl groups, or PEG substituted by guanidinium and sulfhydryl groups (esterified or thioesterified); (ii) in one or more Asp or Glu residues The side chain carboxyl group of the group (if present) with guanidinoalkanol, guanidinoalkanethiol, PEG substituted with guanidino with free hydroxyl groups, or PEG substituted with guanidino and mercapto (esterified or thioesterified) (iii) esterification or thioesterification of the hydroxyl group at one or more Ser, Thr or Tyr residues (if present) with guanidinium alkanoic acid (guanidinium alkanoic acid) or PEG substituted by guanidinium and carboxyl groups ); (iv) sulfhydryl groups at one or more Cys residues (if present) wit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48
CPCC07D323/00B82Y5/00A61K47/48961A61K47/22A61K47/6949A61P13/12A61P5/00
Inventor 保罗·博蒂
Owner 保罗博蒂
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