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Cyclised alpha-conotoxin peptides

A conotoxin peptide, cyclization technology, applied in the field of -V, cyclized α-conotoxin peptide, oral and enteral preparations, can solve the problem of lack of biological feasibility

Inactive Publication Date: 2009-06-03
THE UNIV OF QUEENSLAND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, conotoxin peptide Vc1.1 is considered to lack oral biofeasibility

Method used

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  • Cyclised alpha-conotoxin peptides
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  • Cyclised alpha-conotoxin peptides

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0135] Example 1: Cyclized MII analogs

[0136] (a) Design and synthesis

[0137] The size of the linker required to span the N and C termini of the base MII peptide was determined by known molecular modeling methods. The 3D model of MII was downloaded from Protein Data Bank (PDB). Molecular modeling program, Accelrys is used to determine the appropriate linker length (Insight IIModeling Environment, Release 2000, San Diego, Accelrys Inc. 2001). Briefly, this involves creating an amino acid linker between the N- and C-termini, followed by locking of the conotoxin peptide's structural conformation and simple energy minimization. Next, the structural conformation of the parent conotoxin peptide was unlocked and the structure of the entire peptide was re-minimized. Models with joints that are too small result in structures with higher energies than those with joint lengths that do not affect the underlying structure. It has been determined that the linker spanning the N- to C...

Embodiment 2

[0169] Example 2: Synthesis and Characterization of Cyclized Vc1.1

[0170] (a) Design of cyclized Vc1.1

[0171]α-conotoxin Vc1.1 is a member of class 4 / 7 of α-conotoxins, including MII and has the potential to treat pain (Sandall DW, Satkunanathan N, Keays DA, Polidano MA, Liping X, Pham V, Down JG, Khalil Z, Livett BG, Gayler KR, Biochemistry 2003 42(22):6904-11). There is no structural data of Vc1.1 in the literature, so the design of cyclized MII analogs cannot follow the above steps. However, since the structures of other conotoxins with the same framework have been studied, the optimal linker length for Vc1.1 was estimated from simple distance measurements for other members of this family, including MII and PnIA. In the Protein Data Bank (PDB), there are four structures for α4 / 7 conotoxins in addition to the repeating structure and the conotoxin GID (a structure with an extended flexible "tail" at the N-terminus). The distance values ​​between the N- and C-termini of...

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Abstract

This invention relates to an oral or enteral pharmaceutical preparation comprising at least one synthetically cyclised alpha-conotoxin peptide having an amide cyclised backbone such that the peptide has no free N- or C- terminus, said peptide having the ability to inhibit a nicotinic acetylcholine receptor and comprising four cysteine residues bonded in pairs to form two disulfide bonds, wherein the N-terminus of the corresponding linear / non-cyclised conotoxin peptide is linked to the C-terminus by a peptide linker, in a vehicle which is pharmaceutically suitable for oral or enteral administration.

Description

Background technique [0001] The present invention relates to α-conotoxin peptides, especially cyclized α-conotoxin peptides for the treatment of human diseases. The invention relates in particular to oral and enteral formulations comprising these peptides, the use of these peptides in the manufacture of pharmaceutical formulations, and the use of such pharmaceutical formulations in the prevention or treatment of human conditions or diseases. [0002] Conus (cone snails) sea snails use a complex biochemical trick to catch their prey. As predators of fish, threadworms or other molluscs, cone snails inject their prey with venom containing a cocktail of small bioactive peptides. These toxin molecules, known as conotoxins, interfere with neurotransmission by targeting various ion channels or receptors. They usually contain 12 to 30 amino acids in a linear arrangement. Each cone snail toxin may contain more than 100 different peptides. Conotoxins can be classified according to t...

Claims

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Application Information

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IPC IPC(8): A61K38/12A61K38/16
Inventor R·克拉克D·J·克雷克
Owner THE UNIV OF QUEENSLAND
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