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Conotoxin analog Glu-Con-G[1-13], and design and synthesis method and application thereof

A technology of glu-con-g and conotoxin, which is applied in the direction of drug combination, peptide preparation method, chemical instrument and method, etc., can solve the problems such as difficult to pass the blood-brain barrier, large molecular weight, too long peptide chain, etc., to achieve Speed ​​up the cycle of drug research and development, reduce the number of compounds, and facilitate the effect of artificial synthesis

Inactive Publication Date: 2011-08-31
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, Con-G also has the defects of too long peptide chain, too large molecular weight, and difficulty passing through the blood-brain barrier. In animal experiments, the drug can only be injected by intrathecal injection, which has great limitations in clinical application.

Method used

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  • Conotoxin analog Glu-Con-G[1-13], and design and synthesis method and application thereof
  • Conotoxin analog Glu-Con-G[1-13], and design and synthesis method and application thereof
  • Conotoxin analog Glu-Con-G[1-13], and design and synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1: Sequence Alignment, Homology Modeling and Molecular Docking

[0033] Sequence Alignment, Homology Modeling

[0034] The NMDA receptor NR2B subunit has a total of 1484 amino acids, and the glutamate receptor binding region is 404-802 (S1: D404-N543, S2: K670-H802). Homologous modeling uses the software Modeller 8v2, and uses the Charmm19 standpoint to optimize the modeled structure. The sequence of NR2B subunit (404-802) was obtained from NCBI, and the homologous protein of NR2B was searched by BLAST (PSI-BLAST) according to the sequence, and the reference proteins 2A5S, 1Y20, 1S50 and 2F34 with higher homology were selected, and then carried out Sequence Alignment. Determine the reference protein 2A5S, input the alignment sequence and parameters into the computer, and use Modeller 8v2 to perform homology modeling of NR2B subunits. The Modeller 8v2 program can model multiple target structures, and select better proteins for further optimization according to...

Embodiment 2

[0046] Example 2: Solid phase synthesis and separation and purification of conotoxin Con-G analogue Glu-Con-G[1-13]

[0047] Amino acids were protected with Fmoc (9-fluorenylmethoxycarbonyl) and synthesized on a 433A polypeptide synthesizer (ABI, Foster city, CA). The synthetic peptide resin with side chain protecting groups was used in lysate (composed of: 88% three Fluoroacetic acid (TFA), 5% HO, 2% triisopropylsilane, 5% dimercaptothreitol (fliT)) cleavage, removal of protective groups, and then adding cold ether to precipitate, crude peptide with reversed-phase high-efficiency Purify by liquid chromatography (separation column is cl8 semi-preparative column, Zorabx 300SB, C 10m, qb9.4mm×250mm), gradient elution with water and acetonitrile (both containing 0.1% TFA), collect the target peak, and freeze to obtain pure Taste. Molecular mass was identified by mass spectrometry.

Embodiment 3

[0048] Example 3: Conotoxin Con-G analogue Glu-Con-G[1-13] intervention experiment on CPP

[0049] 1. Materials and methods:

[0050] 11 Establishment of CPP for experimental animals

[0051] 1.1.1 Screening of experimental animals:

[0052] After the animals were adapted to the laboratory (free food and water, natural light, room temperature (22±2)°C, humidity 50%-70%) for 2 weeks, they were marked with saturated picric acid-alcohol solution on different parts of the animal body surface. The experiment was started after 24 h. D-2, d-1, and d0 were tested for natural preference. A channel-type partition was used in the middle of the shuttle box. Animals were placed at the junction channel between the two boxes from above the black box, with their heads facing the white box, allowing them to freely move in the two boxes. Exercise for 15 minutes, record the activity, and analyze its natural preference. Those who met the following criteria twice in the three tests were selected...

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Abstract

The invention discloses a conotoxin analog Glu-Con-G[1-13], which is shorter than a Con-G peptide chain and small in molecular weight, and is obtained by replacing Gla3, Gla4, Gla7, Gla10 and Gla14 of the Con-G by natural amino acid Glu. The invention improves the defect that a Gla residue is hard to obtain to some extent. The Glu-Con-G[1-13] keeps the original activity, namely has certain interference effect on psychological dependence and physical dependence on morphine, is more easily synthesized artificially, and has smaller molecular weight of 1,588; however, the molecular weights of the Con-G and Glu-Con-G are respectively 2,265.19 and 2,044.14.

Description

technical field [0001] The present invention relates to a conotoxin analogue, its design synthesis method and application. Background technique [0002] Cono snails belong to the phylum Molluscs, Gastropoda, and Conidae. Most of them inhabit the shallow waters of tropical oceans. They are named for their conical or taro-shaped shapes. Conus snails are relatively young organisms. Fossil records prove that the genus Conus first appeared in the Eocene (Eocene). speciation. The second large-scale radiation of cone snails began in the Miocene and basically lasted until now (Terlau and Olivera, 2004). [0003] There are about 700 species of cone snails in the world, and the cone snail is one of the most successful evolutionary organisms among marine invertebrates. Although there are many types of cone snails, they are all carnivores and rely on venom to prey on food. Cono snail venom is the main weapon of cone snail predation and defense. It is a cocktail-like mixed toxin comp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/08C07K1/04A61K38/10A61P25/30A61P25/04
Inventor 朱永平陈翔周晚玲许洁琼钱玲玲徐艳兰王华谌程任展宏
Owner ZHEJIANG UNIV
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