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Peptide with neuroprotective effect, preparation method thereof, pharmaceutical composition and purpose

A technology of neuroprotection and composition, which is applied in the field of biomedicine, can solve problems such as failure, and achieve the effect of good application prospects

Inactive Publication Date: 2014-11-12
XUZHOU MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although CEP1347 and CEP11004 are MLK3 inhibitors, they inhibit the overactivated MLK3 in pathological conditions and also inhibit the physiological function of MLK3, and failed in phase II clinical trials (Parkinson Study Group PRECEPT Investigators.Neurology 2007; 69: 1480- 1490)

Method used

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  • Peptide with neuroprotective effect, preparation method thereof, pharmaceutical composition and purpose
  • Peptide with neuroprotective effect, preparation method thereof, pharmaceutical composition and purpose
  • Peptide with neuroprotective effect, preparation method thereof, pharmaceutical composition and purpose

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1 Inhibitory effect of P2 on neurotoxicity induced by β-amyloid peptide (Aβ)

[0042] The inventor's previous research results have proved that Aβ can induce the apoptosis of neurons, and the MLK3-MKK7-JNK3 signaling pathway is involved in the apoptosis of neurons induced by Aβ (see Xu Y, Hou XY, *Liu Y, and Zong YY.Journal of Neuroscience Research, 2009, 87:918-927), so this example studies whether the test peptides P1, P2 and P3 can inhibit the apoptosis of neurons induced by Aβ.

[0043] Pregnant 17-19 days SD rats (clean grade, purchased from Shanghai Sippr-BK Company) were killed by decapitation, and the fetal rats were quickly taken into ice-cold high-glucose DMEM, the cortex was stripped under a stereoscope, and digested with 0.25% trypsin , dispersed into single cells after terminating the reaction, and counted at 0.5×10 5 / cm 2 Inoculate in polylysine-pretreated culture flasks or culture plates, replace the serum-free medium every 3-4 hours, and cha...

Embodiment 2

[0053] Example 2 P2 specific inhibition of Aβ-induced binding of MLK3 and PSD-95

[0054] PSD-95 is a scaffold protein that can bind a variety of signaling proteins. PSD-95 binds N-methyl-D-aspartate (NMDA) receptor subunit 2A (NR2A), human seaweed Acid receptor subunit (GluK2), Src kinase; PSD-95 binds MLK3, proline-rich tyrosine protein kinase 2, etc. through its SH3 domain. To test whether P2 inhibits the binding of PSD-95 to other signaling proteins while inhibiting the binding of PSD-95 and MLK3, the following experiments were performed:

[0055] COS7 cells (purchased from Shanghai Cell Bank, Chinese Academy of Sciences) were cultured in DMEM containing 10% fetal bovine serum. Among them, the COS7 cells were divided into 2×10 6 / ml inoculated in Petri dishes, in 5% CO 2 After culturing in the incubator for 24 hours until the density of COS7 cells was about 80-90%, LipofectAMINE2000 (Invitrogen) was used to co-transfect the COS7 cells expressing NR2A and PSD-95, GluR6...

Embodiment 3

[0059] Example 3 The protective effect of P2 on hippocampal neuron injury

[0060] Neurons in the CA1 region of the rat hippocampus are the most sensitive region to global cerebral ischemia-reperfusion injury. In order to detect whether P2 has a protective effect on hippocampal neuron injury induced by global cerebral ischemia-reperfusion in rats, the following experiments were carried out:

[0061] The four-artery ligation method was used to establish a model of global cerebral ischemia in SD rats with four-arterial ligation referring to Liu Y et al., Brain Res, 2001, 909: 51-58, in which the global cerebral ischemia was 15 minutes, and the intracerebroventricular injection was performed before ischemia Drug to be tested or control drug. On the 5th day of cerebral ischemia-reperfusion, tar violet staining was used to observe the effect of injected drugs on the survival of pyramidal neurons in CA1 region of hippocampus after ischemia-reperfusion injury. The specific operati...

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Abstract

The invention provides a peptide, a nucleotide sequence coding the peptide, a pharmaceutical composition containing the peptide, and pharmaceutical purpose of the peptide. An amino acid sequence of the peptide provided by the invention is as shown in SEQ. ID. NO. 1. The peptide can interfere combination of MLK3 with PSD-95, inhibit activation of the MLK3 and cellular signal transduction at the downstream of the MLK3 during a neuronal apoptosis process, thereby resulting in neuroprotection and having a good medicament application prospect.

Description

technical field [0001] The invention belongs to the field of biomedicine, in particular, the invention relates to a peptide with neuroprotective effect, its preparation method, a pharmaceutical composition containing the peptide and the pharmaceutical use of the peptide. Background technique [0002] MLK3 (Mixed lineage kinase, Mixed lineage kinase 3) is a member of the MLKs subfamily of the MAPKKK (mitogen-activated protein kinase kinase kinase) family, which activates the filament / Threonine protein kinase is an important kinase upstream of JNK3 (c-Jun N-terminal kinase family member) (Gallo KA et al., Nature reviews, September 2002, 3(9): 663-72; Ip YT et al., Curr Opin Cell Biol, 1998, 10:205-219). MLK3 is composed of SH3 (Src homology 3) domain, kinase domain, leucine zipper domain, and Cd4c2 / Rac interaction domain. It can undergo autophosphorylation through threonine 277 and serine 281, and The autophosphorylation of MLK3 is closely related to its activation through ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/08C12N15/11C12N15/63A61K38/10A61K48/00A61P25/00A61P25/08A61P25/16A61P25/28A61P29/00A61P37/02
Inventor 侯筱宇李婷徐珍张晓红徐岩胡斌
Owner XUZHOU MEDICAL COLLEGE
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