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New stapled-peptides and uses thereof

一种用途、模拟肽的技术，应用在作为炎症通路抑制剂领域，能够解决不允许阻断上游炎症通路、抗体繁重处理等问题

Inactive Publication Date: 2019-09-17
UNIVERSITY OF MONTPELLIER +4
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, antibodies are processing-heavy and do not allow blocking of upstream inflammatory pathways

Method used

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  • New stapled-peptides and uses thereof
  • New stapled-peptides and uses thereof
  • New stapled-peptides and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0216] Example 1: Preparation and Characterization of Staple Peptides IRAK2 and IRAKM

[0217] 1.1 Synthesis of stapled peptides with hydrocarbon bridges

[0218] Synthesis of IRAK2 and IRAKM stapled peptides was performed manually by the SPPS method. The synthesis scale was 0.1 mmol, and 40-RAM amphiphilic Rink amide resin was loaded at 0.4 mmol / g, with an excess of 5 equivalents for the protected amino acid. All protected amino acids and the coupling agent O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) were pre-dissolved in DMF to prepare a stock solution at a concentration of 0.5M. Under vortex stirring, the resin was first swelled in 6ml DMF for 15 minutes. After removal of DMF by filtration, deprotection of the Fmoc group was performed by adding a 20% piperidine / DMF solution (6 ml) and vortexing for 1 min. This is done twice. The resin was washed 3 times with DMF. Add the desired amino acid (1ml, 0.5mmol), N,N-diisopropylethyl...

Embodiment 2

[0228] Example 2: Evaluation of the specificity and efficacy of stapled peptides against the IRAK2 target

[0229] 2.1 Activation of endoplasmic reticulum stress (ER stress)

[0230] In cells, most secreted and membrane proteins are synthesized in the ER, where they are folded and assembled prior to transport. Under certain conditions, abnormal conformational proteins accumulate in the endoplasmic reticulum (ER), inducing stress (ER stress) and UPR (unfolded protein response). ER stress also contributes to the inflammatory response by differently activating the transcription of NF-κB transcription factors and inflammatory genes (pro-inflammatory cytokines). The UPR response involves activation of transcription of target genes and profound repression of translation, which increases folding and degradation capacity and limits the arrival of new proteins in the ER. Studies have shown that the IRAK2 molecule is essential for the induction of both ER stress (Benosmab et al. P...

Embodiment 3

[0243] Example 3: Evaluation of the efficacy of the stapled peptides IRAK2-S1 and IRAK-M-S1 under three different conditions: simultaneous, therapeutic sexual or prophylactic treatment

[0244] The previous examples show that staple peptide mimics the action of the natural Mydd body inhibitor IRAK-M. Indeed, it was demonstrated that exposure of THP1 monocytes to the staple peptides IRAK2-S1 and IRAKM-S1 6 h after LPS stimulation reproduced the LPS-tolerant condition, i.e. suppressed IL-6 and TNFα cytokine production. This example investigates whether different experimental setups can show better results. Three different conditions of LPS stimulation were compared: simultaneous LPS stimulation of monocytes and addition of stapled peptide (simultaneous condition: A), 6 hours before LPS stimulation (preventive condition: B) or 6 hours after ( Therapeutic conditions: C) adding staple peptide ( Figure 6 ).

[0245] For all tested conditions, THP-1 mononuclear cells (300000 ...

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Abstract

The present invention relates to peptidomimetic macrocycles comprising at least one macrocycle-forming linker and an amino acid sequence chosen from the group consisting of : i) an amino acid sequence with at least about 50%, 60%, 70%, 80%, 90%, or 95% sequence identity to a human sequence IRAK2 54-71 (SEQ ID No.1) and 100% identity with the amino acids in the positions 5-6, 9-11, 14-15 or ii) an amino acid sequence with at least about 50%, 60%, 70, 80%, 90%, or 95% sequence identity to a human sequence IRAKM 66-83 (SEQ ID No.2) and 100% identity with the amino acids in the positions 5-6, 9-11, 13-14, wherein the peptidomimetic macrocycle comprises an a-helix and at least two natural or two non-natural amino acids crosslinked by a macrocycle-forming linker. It also concerns method of preparation of said peptidomimetic macrocycles and uses thereof, pharmaceutical composition and uses thereof, in particular as inhibitors of inflammatory pathways.

Description

technical field [0001] The present invention provides novel peptidomimetic macrocycles, also known as stapled peptides, derived from the protein binding region of IRAK2 and IRAKM (also known as IRAK3) IRAK4, and their uses, in particular their use as inflammatory pathway inhibitors use of the agent. [0002] The term "IRAK" as used herein refers to an interleukin-receptor-associated kinase which is associated with an interleukin receptor (IL-R) upon stimulation. The IRAK gene is partially responsible for interleukin-induced upregulation of the transcription factor NF-κB. Background technique [0003] Toll-like receptor (TLR) signaling is central to host defense against many pathogenic microorganisms and underlies the enormous burden of human disease, including chronic inflammatory disorders. [0004] Inflammatory disorders and autoimmune diseases are important public health problems that affect the lives of millions of people worldwide and require specific therapeutic inte...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/00C12N9/12A61K38/00
CPCA61K38/00C07K14/7155C07K14/00C12N9/12A61P1/04A61P19/02A61P25/00A61P29/00A61P31/04A61P31/06A61P31/10A61P31/12A61P33/00A61P35/00A61P3/10A61P37/06A61P43/00A61P9/00A61K45/06C07K7/08
Inventor G·拉孔达M·安布拉尔-科西J·马丁斯C·乔根森F·阿帕莱尔-塞尚I·迪鲁-理查德
Owner UNIVERSITY OF MONTPELLIER
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