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Influence of Disulfide Connectivity on Structure and Bioactivity of α-Conotoxin TxIA
- Source :
- Molecules, Vol 19, Iss 1, Pp 966-979 (2014), Molecules, Volume 19, Issue 1, Pages 966-979
- Publication Year :
- 2014
- Publisher :
- MDPI AG, 2014.
-
Abstract
- Cone snails express a sophisticated arsenal of small bioactive peptides known as conopeptides or conotoxins (CTxs). Through evolutionary selection, these peptides have gained the ability to interact with a range of ion channels and receptors, such as nicotinic acetylcholine receptors (nAChRs). Here, we used reversed-phase high performance liquid chromatography (RP-HPLC) and electrospray ionization-mass spectrometry (ESI-MS) to explore the venom peptide diversity of Conus textile, a species of cone snail native to Hainan, China. One fraction of C. textile crude venom potently blocked α3β2 nAChRs. Subsequent purification, synthesis, and tandem mass spectrometric analysis demonstrated that the most active compound in this fraction was identical to α-CTx TxIA, an antagonist of α3β2 nAChRs. Then three disulfide isoforms of α-CTx TxIA were synthesized and their activities were investigated systematically for the first time. As we observed, disulfide isomerisation was particularly important for α-CTx TxIA potency. Although both globular and ribbon isomers showed similar retention times in RP-HPLC, globular TxIA potently inhibited α3β2 nAChRs with an IC50 of 5.4 nM, while ribbon TxIA had an IC50 of 430 nM. In contrast, beads isomer had little activity towards α3β2 nAChRs. Two-step oxidation synthesis produced the highest yield of α-CTx TxIA native globular isomer, while a one-step production process based on random oxidation folding was not suitable. In summary, this study demonstrated the relationship between conotoxin activity and disulfide connectivity on α-CTx TxIA.
- Subjects :
- Spectrometry, Mass, Electrospray Ionization
Conus textile
Stereochemistry
Pharmaceutical Science
Peptide
Venom
Nicotinic Antagonists
Receptors, Nicotinic
Article
α-conotoxinTxIA
Membrane Potentials
Analytical Chemistry
Cone snail
lcsh:QD241-441
Structure-Activity Relationship
Xenopus laevis
α-conotoxin TxIA
chemistry.chemical_compound
α3β2 nAChRs
lcsh:Organic chemistry
peptide synthesis
Drug Discovery
Peptide synthesis
Animals
Conotoxin
Physical and Theoretical Chemistry
Cells, Cultured
Chromatography, High Pressure Liquid
Ion channel
disulfide isomerisation
chemistry.chemical_classification
Chromatography, Reverse-Phase
biology
Oxidative folding
Organic Chemistry
Conus Snail
biology.organism_classification
Rats
chemistry
Chemistry (miscellaneous)
oxidative folding
Cystine
Molecular Medicine
Conotoxins
Subjects
Details
- ISSN :
- 14203049
- Volume :
- 19
- Database :
- OpenAIRE
- Journal :
- Molecules
- Accession number :
- edsair.doi.dedup.....b49a589a91d38c09329b8479184f49f8