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Molecules 2014, 19(1), 966-979; doi:10.3390/molecules19010966

Influence of Disulfide Connectivity on Structure and Bioactivity of α-Conotoxin TxIA

Key Laboratory of Tropical Biological Resources, Ministry of Education, Key Lab for Marine Drug of Haikou, Hainan University, Haikou, Hainan 570228, China
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Received: 8 November 2013 / Revised: 7 January 2014 / Accepted: 9 January 2014 / Published: 15 January 2014
(This article belongs to the Section Natural Products)
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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.
Keywords: α-conotoxin TxIA; α3β2 nAChRs; disulfide isomerisation; peptide synthesis; oxidative folding α-conotoxin TxIA; α3β2 nAChRs; disulfide isomerisation; peptide synthesis; oxidative folding
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Wu, Y.; Wu, X.; Yu, J.; Zhu, X.; Zhangsun, D.; Luo, S. Influence of Disulfide Connectivity on Structure and Bioactivity of α-Conotoxin TxIA. Molecules 2014, 19, 966-979.

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