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Polypeptide with nNOS-Capon uncoupling activity and application of polypeptide

A technology of uncoupling and che-gly-asp, which is applied in the field of polypeptides with nNOS-Capon uncoupling activity, can solve the problem that NMDAR antagonists cannot develop therapeutic drugs, and achieve obvious neuroprotective effects

Active Publication Date: 2020-08-14
NANJING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, clinical studies have shown that NMDAR antagonists cannot be developed into therapeutic drugs due to their side effects

Method used

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  • Polypeptide with nNOS-Capon uncoupling activity and application of polypeptide
  • Polypeptide with nNOS-Capon uncoupling activity and application of polypeptide
  • Polypeptide with nNOS-Capon uncoupling activity and application of polypeptide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1 N-Cyclohexylethyl-Ala-Glu-Ala-Val (Che-AEAV)

[0050] After activating the dry 2-chlorotrimethyl chloride resin (loading rate 1.056mmol), use Fmoc-Val-OH as the starting material, repeat the Fmoc removal and amino acid condensation reaction many times, the specific synthetic route is as follows figure 2 As shown, 155.5 mg of Che-AEAV was obtained with a yield of 15.61%. HPLC:t R =13.45min.MS(ESI)calcd for C 24 h 42 N 4 o 7 [M-H] - :497.3; found: m / z 497.3. 1 H NMR (300MHz, DMSO-d 6 )δ12.30(s, 2H), 8.64(d, J=8.3Hz, 1H), 8.07(d, J=7.1Hz, 1H), 7.90(d, J=8.6Hz, 1H), 4.34(t, J=7.0Hz, 2H), 4.10(dd, J=8.5, 5.7Hz, 1H), 3.89(s, 1H), 2.78(s, 3H), 2.24(t, J=8.0Hz, 2H), 2.01– 1.89(m,1H),1.87(d,J=5.2Hz,1H),1.83–1.68(m,1H),1.61–1.47(m,5H),1.42(t,J=7.6Hz,2H),1.33 (d,J=6.8Hz,3H),1.18(d,J=7.0Hz,6H),0.84(d,J=6.8Hz,9H).

Embodiment 2

[0051] Example 2 N-Cyclohexylethyl-Ala-Glu-Trp-Val (Che-AEWV)

[0052] According to the synthesis method in Example 1, 76.3 mg of Che-AEWV was obtained with a yield of 12.45%. HPLC:t R =14.15min.MS(ESI)calcd for C 32 h 47 N 5 o 7 [M-H] - :612.3; found: m / z 612.4. 1 H NMR (300MHz, DMSO-d 6 )δ13.04–11.60(m,2H),10.75(s,1H),8.58(d,J=8.5Hz,1H),8.08(t,J=8.5Hz,2H),7.82–6.38(m,5H ), 4.65(d, J=4.9Hz, 1H), 4.33(d, J=5.4Hz, 1H), 4.21–4.06(m, 1H), 3.81(d, J=7.0Hz, 1H), 3.09(d ,J=10.0Hz,2H),2.97–2.63(m,3H),2.15–2.05(m,3H),2.06(s,1H),1.87(s,1H),1.73(d,J=7.9Hz, 1H), 1.60(d, J=9.5Hz, 5H), 1.55–1.32(m, 3H), 1.23–1.12(m, 4H), 1.13(s, 3H), 0.87–0.71(m, 6H).

Embodiment 3

[0053] Example 3 N-Cyclohexylethyl-Ala-Asp-Trp-Val (Che-ADWV)

[0054] According to the synthesis method in Example 1, 38.4 mg of Che-ADWV was obtained with a yield of 6.41%. HPLC:t R =14.35min.MS(ESI)calcd for C 31 h 45 N 5 o 7 [M-H] - :598.3; found: m / z 598.3. 1 H NMR (300MHz, DMSO-d 6 )δ10.75(s,2H),8.66(s,1H),7.96(s,2H),7.55(d,J=7.8Hz,1H),7.28(d,J=8.4Hz,1H),7.13– 6.77(m,4H),4.58(s,2H),4.12(s,1H),3.68(s,1H),3.08(s,2H),2.93(s,2H),2.67–2.35(m,3H) ,2.01(s,1H),1.58(s,5H),1.38(d,J=7.5Hz,3H),1.23(d,J=6.8Hz,5H),1.12–0.99(m,3H),0.84( d,J=4.1Hz,6H).

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Abstract

The invention discloses a polypeptide with nNOS-Capon uncoupling activity and an application of the polypeptide. The polypeptide is characterized in that a structural general formula of the amino acidsequence is Che-Xaa1-Xaa2-Xaa3-Val, wherein the Che is equal to N-Cyclohexylethyl, the Xaa1 is equal to Ala or Gly, the Xaa2 is equal to Glu, Glu (OMe), Asp or Asp (OMe), and the Xaa3 is equal to modified or natural amino acid. The polypeptide has nNOS-Capon uncoupling activity, and can be used as a neuroprotective agent for treating cerebral arterial thrombosis. The invention provides a fluorescence polarization method (FP) for rapidly screening nNOS-Capon uncoupling activity in vitro. The polypeptide screened by the FP method has an obvious neuroprotective effect on a rat cerebral ischemiareperfusion model (MACO).

Description

technical field [0001] The invention belongs to the field of pharmacy, and specifically relates to a polypeptide with nNOS-Capon uncoupling activity and application thereof. Background technique [0002] Ischemic stroke is one of the most disabling and fatal diseases in the world and seriously endangers human health. The development of its therapeutic drugs is one of the most important topics in medicinal chemistry. At present, research on stroke drugs mainly includes: calcium channel antagonists, glutamate release inhibitors, GABA receptor agonists, nNOS inhibitors, free radical scavengers, MMP-9 inhibitors, NMDAR antagonists, etc., but treatment The effects are not ideal. Many neuroprotective agents that are effective in animal models of stroke have failed to achieve the expected efficacy in human clinical trials or had to terminate clinical trials due to excessive side effects. [0003] When ischemic stroke occurs, the toxic effects of excitatory amino acids (EAA) play ...

Claims

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Application Information

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IPC IPC(8): C07K5/103C07K1/04A61K38/08A61P25/00A61P9/10A61P25/22A61P25/24
CPCC07K5/1008A61P25/00A61P9/10A61P25/22A61P25/24A61K38/00
Inventor 秦亚娟厉廷有冯玲玲徐剑郑礼平
Owner NANJING MEDICAL UNIV
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