Abstract
Integrated venomics techniques have shown that variable processing of conotoxins from Conus marmoreus resulted in a dramatic expansion in the number of expressed conotoxins. One conotoxin from C. marmoreus, the χ-conotoxin MrIA, is a selective inhibitor of human norepinephrine transporters (hNET) and therefore a drug candidate for attenuating chronic neuropathic pain. It has been found that “messy” processing of the MrIA transcripts results in the expression of MrIA analogs with different truncations of the pro-peptide that contains portions of the MrIA molecule. The aim of this study was to investigate if variable processing of the expressed peptides results in modulation of the existing hNET pharmacology or creates new pharmacologies. To this end, a number of MrIA analogs found in C. marmoreus venom were synthesized and evaluated for their activity at hNET receptors. While several of the analogs exhibited norepinephrine transporter inhibitory activity comparable to that of MrIA, none significantly improved on the potency of conotoxin MrIA, and those analogs with disrupted pharmacophores produced greatly reduced NET inhibition, confirming previous structure-activity relationships seen on χ-class conopeptides. Additionally, analogs were screened for new activities on ion channels using calcium influx assays, although no major new pharmacology was revealed.
Highlights
Cone snails represent a large taxon of carnivorous gastropods that use specialized venom to hunt fish, worms, or fellow molluscs
This molecular diversity is possible via variable peptide processing (VPP), in which the use of alternative cleavage sites, post-translational modifications (PTMs), and variable N- and C-terminal truncations create a plethora of peptides from a single gene precursor, resulting in biological “messiness” at the proteomic level
MrIA were identified via proteomic methods that corresponded to various peptides originating from inhibits norepinephrine transporters
Summary
Cone snails represent a large taxon of carnivorous gastropods that use specialized venom to hunt fish, worms, or fellow molluscs. The venom of these snails is prolific with small, disulfide-rich peptides that bind to various physiological targets. It has been found that in a single species of cone snail, approximately only 100 genes are responsible for producing thousands of peptides [4]. This molecular diversity is possible via variable peptide processing (VPP), in which the use of alternative cleavage sites, post-translational modifications (PTMs), and variable N- and C-terminal truncations create a plethora of peptides from a single gene precursor, resulting in biological “messiness” at the proteomic level. Of particular interest was the gene coding for the χ-conotoxin MrIA (sequence NGVCCGYKLCHOC-NH2) because
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