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Alpha-conotoxins from Hainan province for specific blockage of acetylcholine receptor and application thereof

A conotoxin and specific technology, applied in the field of α-conotoxin peptides produced in Hainan, can solve the problems that research and development have not yet been carried out

Inactive Publication Date: 2010-06-23
HAINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the α-CTXs that have been involved in research so far account for less than 0.1% of the total
In particular, the research and development of α-conotoxin in Hainan snails has not yet been carried out

Method used

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  • Alpha-conotoxins from Hainan province for specific blockage of acetylcholine receptor and application thereof
  • Alpha-conotoxins from Hainan province for specific blockage of acetylcholine receptor and application thereof
  • Alpha-conotoxins from Hainan province for specific blockage of acetylcholine receptor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] The one-step oxidation synthesis of embodiment 1α-conotoxin LtIA, TxIB

[0065] According to the amino acid sequences of α-conotoxins LtIA and TxIB, the linear peptides of these two polypeptides were artificially synthesized by Fmoc and FastMoc chemical methods, and oxidatively folded. The specific method is as follows.

[0066] Two conotoxin linear peptides, LtIA and TxIB, were synthesized on the ABI Prism 433a peptide synthesizer by using the Fmoc and FastMoc methods in the solid-phase synthesis method. The side chain protecting groups of Fmoc amino acids are: Pmc(Arg), Trt(Cys), But(Thr, Ser, Tyr), OBut(Asp), Boc(Lys). Using Fmoc HOBT DCC method, Rink amidation resin and Fmoc Amino acids, all cysteines (Cys) are protected by Trt, and the synthesis steps are carried out with reference to the instrument synthesis manual. In order to complete the reaction, the piperidine deprotection and coupling time are appropriately prolonged, and the difficult amino acid is double...

Embodiment 2

[0068] The two-step oxidation synthesis of embodiment 2α-conotoxin LtIA, TxIB

[0069] The resin peptides of LtIA and TxIB are artificially synthesized by Fmoc chemical method. Except for cysteine, the other amino acids use standard side chain protection groups. The synthesis steps are the same as the one-step oxidation synthesis. The -SH of the 1st and 3rd cysteine ​​is protected with Trt (S-trityl), and the -SH of the 2nd and 4th cysteine ​​is protected with Acm (S-acetamidomethyl) paired cross-protection, resin peptide The linear peptide with Acm was obtained by cleavage and recovery in the same way as the one-step oxidation method. References McIntosh, J.M., Azam, L., Staheli, S., Dowell, C., Lindstrom, J.M., Kuryatov, A., Garrett, J.E., Marks, M.J., and Whiteaker, P. (2004) Analogs of α- ConotoxinMII Are Selective for α6-Containing Nicotinic Acetylcholine Receptors. Two-step oxidation method of MolPharmacol 65, 944-952 for selective oxidative folding of linear peptides o...

Embodiment 3

[0070] Example 3 α-conotoxin LtIA is a specific inhibitor of α3β2nAChRs

[0071] Refer to Azam L, Yoshikami D, McIntosh JM.Amino acid residues that confer high selectivity of the alpha6 nicotinicacetylcholine receptor subunit to alpha-conotoxinMII[S4A, E11A, L15A].J Biol Chem.2008Apr 25;283(17):11625 The method in Epub 2008Feb 25, as well as the in vitro transcription kit (mMessage mMachinein vitro transcription kit (Ambion, Austin, TX)) instructions, prepared various rat neurotype nAChRs subtypes (α3β2, α6 / α3β2β3, α6 / α3β4, α9α10 , α4β2, α4β4, α3β4, α2β2, α2β4, α7), α3β2 nAChRs mutant (α3β2T59K, α3β2V111I, α3β2F119Q), and mouse muscle nAChRs (α1β1δε) cRNA, the concentration was measured by OD value under UV 260nm. Xenopus laveis oocytes (frog eggs) were collected by dissection, and cRNA was injected into the frog eggs, and the injected amount of each subunit was 5 ng cRNA. Injection of 0.5 to 2.5 ng DNA per subunit of muscle nAChR. Frog eggs were cultured in ND-96. cRNA was...

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Abstract

The invention relates to alpha-conotoxins from Hainan province for specific blockage of a acetylcholine receptor and application thereof, in particular to application of alpha-conotoxins LtIA for specific blockage of (alpha)2(beta)3. nAChRs, application of alpha-conotoxins TxIB for specific blockage of (alpha)9(beta).10 nAChRs, related pharmaceutical compositions and the like.

Description

technical field [0001] The present invention relates to Hainan-produced α-conotoxin peptide capable of specifically blocking acetylcholine receptors (nAChRs) and its use. nAChRs are key receptors with important physiological functions and clinical research significance, mediating many physiological functions of the central and peripheral nervous systems, including learning, memory, response, analgesia and motor control. Background technique [0002] Nicotinic acetylcholine receptors (nAChRs), which have important physiological roles and clinical research significance, mediate many physiological functions of the central and peripheral nervous systems, including learning, memory, response, analgesia, and motor control. nAChRs activate the release of various neurotransmitters such as dopamine, norepinephrine, serotonin, and γ-aminobutyric acid. It has been confirmed that nAChRs are the key targets for the screening, diagnosis and treatment of a large class of drugs for importa...

Claims

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Application Information

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IPC IPC(8): A61K38/10A61P25/00A61P25/04A61P25/16A61P25/28A61P29/02
Inventor 罗素兰长孙东亭吴勇朱晓鹏冯建成张本保罗·F·阿莱温奥德J·迈克尔·麦克托什
Owner HAINAN UNIVERSITY
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