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Modified peptides and their use for treating autoimmune diseases

A technology for autoimmune diseases and immunosuppression, applied in the field of modified peptides, which can solve the problems of peptide instability and inactivity

Active Publication Date: 2014-10-22
CENT NAT DE LA RECHERCHE SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, further experiments have shown that the peptides disclosed in WO 03 / 020747 and WO 03 / 025014 are relatively unstable and are rapidly cleared when administered to mammals
Furthermore, some of the peptides disclosed are inactive

Method used

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  • Modified peptides and their use for treating autoimmune diseases
  • Modified peptides and their use for treating autoimmune diseases
  • Modified peptides and their use for treating autoimmune diseases

Examples

Experimental program
Comparison scheme
Effect test

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[0141] Statistics

[0142] Statistical tests were performed using GraphPad Prism version 5.0. The statistical significance of the difference in urine protein between control and peptide-treated mice was analyzed using a two-way ANOVA test. The survival rate of control and P140 analogue-treated female MRL / lpr mice was analyzed by Kaplan-Meier method, and the significance of the difference was determined by Log-Rank test. For other variables, statistical significance was assessed using Student's t-test. A p-value less than 0.05 was considered significant.

Embodiment 1

[0143] Example 1 Chemical synthesis of peptides.

[0144] P140 peptide and P140(MO) were synthesized by classical fluorenylmethoxycarbonyl (N-[9-fluorenyl]methoxycarbonyl) solid-phase chemistry and purified by reverse-phase high-performance liquid chromatography (HPLC; Neimark and Briand, 1993 ; Monneaux et al., 2003, Eur. J. Immunol. 33, 287-296; Page et al., 2009, PloS ONE 4, e5273). Their homogeneity was checked by analytical HPLC and their identity assessed by LC / MS on a Finnigan LCQ Advantage Max system (Thermo Fischer Scientific). After the reaction was complete, the peptide was purified by HPLC.

[0145] To introduce phosphorylation at the position of the serine residue corresponding to residue 140 of sequence 3, a serine derivative of the Fmoc-Ser(PO(Obz)OH)-OH-type was used. The connection time was increased to 30 min, and a second connection was performed systematically. After unraveling in acid medium, each peptide was precipitated by cold ether, dissolved in wat...

Embodiment 2

[0147] Example 2 Peptide Stability.

[0148] At 37°C, sequence 2 (wherein the serine at position 10 is phosphorylated and the methionine at position 4 is oxidized (P140(MO)) and sequence 1 (wherein the serine at position 10 is oxidized) is determined in 10% (v / v) mannitol solution. Stability of peptides that were phosphorylated (P140). Three concentrations were tested for each peptide: 200, 100 and 50 μg / mL.

[0149] At the indicated times, the integrity of the P140 and P140(M(O) peptides was determined from the peak areas corresponding to the intact peptides by HPLC in saline solution.

[0150] The result is as figure 1 shown.

[0151] Tables 1 and 2 below summarize the results:

[0152] Table 1:

[0153]

[0154] Table 2:

[0155]

[0156] Stability was determined by using HPLC peak surfaces.

[0157] P140M(O) stability remained unchanged (100%, 99.1% and 99.4%) for each concentration tested (50 to 200 μg / ml) over 100 days at 37°C.

[0158] At 37°C, P140 stabilit...

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Abstract

The present invention relates to a peptide, or a salt thereof, comprising or consisting of the amino acid sequence IHMVYSKRSGKPRGYAFIEY, comprising one or more post- translational modifications.

Description

technical field [0001] The invention relates to a modified peptide and its use for treating autoimmune diseases. [0002] merge by reference [0003] A Sequence Listing containing Serial Numbers 1-6 is filed herewith, which is hereby incorporated by reference in its entirety. Background technique [0004] Autoimmune diseases result from an overactive immune response of the immune system to normal substances and tissues present in multicellular organisms, ie the immune system attacks its own components. This may be limited to certain organs or involve specific tissues in different places. Treatment of autoimmune diseases generally uses immunosuppressive drugs, which reduce the overall immune response. [0005] Lupus is an autoimmune disease estimated to affect nearly 1.4 million Americans, primarily women aged 20-40. Lupus involves antibodies that attack connective tissue. The predominant form of lupus erythematosus is systemic (systemic lupus erythematosus; SLE). SLE i...

Claims

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Application Information

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IPC IPC(8): A61K38/04C07K7/08
CPCC07K7/08C07K14/47A61K38/00A61K38/1709A61P1/04A61P17/00A61P19/02A61P25/00A61P29/00A61P37/02A61P37/06A61P3/10A61K38/04A61K38/10
Inventor S·米勒J-P·白里安R·齐默尔
Owner CENT NAT DE LA RECHERCHE SCI