Two new classes of conopeptides inhibit the α1-adrenoceptor and noradrenaline transporter

Abstract

Cone snails use venom containing a cocktail of peptides ('conopeptides') to capture their prey. Many of these peptides also target mammalian receptors, often with exquisite selectivity. Here we report the discovery of two new classes of conopeptides. One class targets alpha1-adrenoceptors (rho-TIA from the fish-hunting Conus tulipa), and the second class targets the neuronal noradrenaline transporter (chi-MrIA and chi-MrIB from the mollusk-hunting C. marmoreus). rho-TIA and chi-MrIA selectively modulate these important membrane-bound proteins. Both peptides act as reversible non-competitive inhibitors and provide alternative avenues for the identification of inhibitor drugs.

Subtype-selective Noncompetitive or Competitive Inhibition of Human α1-Adrenergic Receptors by ρ-TIA

“…This highly charged peptide (amino acid sequence FN-WRCCLIPACRRNHKKFC) forms a distinct structure with two disulfide bonds between cysteines 5 and 11 and cysteines 6 and 19 (26). -TIA was found to be a selective ␣ 1 -AR antagonist, as it inhibited ␣ 1 -AR-mediated contraction of rat vas deferens without affecting ATP or ␣ 2 -AR-mediated responses (26,27).…”

“…Recently, a 19-amino acid conopeptide, -TIA, was isolated from the venom of the fish-hunting cone snail Conus tulipa (26,27). This highly charged peptide (amino acid sequence FN-WRCCLIPACRRNHKKFC) forms a distinct structure with two disulfide bonds between cysteines 5 and 11 and cysteines 6 and 19 (26).…”

Developmental Biology of Neoplastic Growth

“…χ-Conopeptides first isolated from C. marmoreus (Fig. 2) are highly specific, non-competitive inhibitors of norepinephrine uptake through the NET (Sharpe et al 2001) that produce potent anal- …”

“…This peptide has a cysteine spacing and structure reminescent of the α-conotoxins, but its novel sequence allows it to selectively target mammalian α 1A -, α 1B -and (Nilsson et al 2005). An analogue of χ-MrIA, with the unstable asparagine replaced with a pyroglutamate (named Xen2174), is currently in the clinical in a Phase I/IIa trial in severe cancer pain patients Paczkowski et al (2007) with permission α 1D -adrenoceptors (Sharpe et al 2001). Interestingly, TIA noncompetitively inhibits α 1B -adrenoceptors but competitively inhibits α 1A -and α 1D -adrenoceptors (Sharpe et al 2003;Chen et al 2004).…”

“…Brevetoxins are accumulated by filter-feeding shellfish and can cause the syndrome neurotoxic shellfish poisoning in those persons that eat brevetoxin contaminated mollusks. Ciguatoxin is accumulated through the oceanic food chain with ciguatoxic fish causing debilitating and long lasting effects in humans (Gatti et al 2008;Lewis 2001).…”