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.
Highlights
Cone snail venoms represent a vast untapped reservoir of natural products that have potential medicinal value for pharmaceutical development
The crude venom extracted from Hainan C. textile was fractionated by reversed-phase high performance liquid chromatography (RP-HPLC) and more than 90 peaks were detected (Figure 2A)
C. textile venom contains numerous distinct peptides, providing new information on C. textile venom complexity and diversity
Summary
Cone snail venoms represent a vast untapped reservoir of natural products that have potential medicinal value for pharmaceutical development. Various species of marine cone shells have been estimated to produce over 50,000 distinct neurologically active peptides [1,2]. Analysis of these natural toxins may help identify model compounds for the discovery of novel therapeutic agents [3,4,5]. These toxins gain the ability to interact with various ion channels and receptors, such as nicotinic acetylcholine receptors (nAChRs) [3]. The compound with same molecular mass as the known antagonist of α3β2 nAChRs, α-CTx TxIA, showed highest potency [8]
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