8.B.4 The Conotoxin T (Conotoxin) Family
Numerous natural toxins have evolved to target sodium channels, either by blocking current through the pore or by modifying channel gating. Among the well studied toxins, the peptide conotoxins from cone snail venoms show a remarkable ability to discriminate among closely related forms of sodium channel, as well as exhibiting a variety of modes of action. The molecular basis of action of different Na channel targeted conotoxins have been reported, and their potential as models for the future design of more specifically targeted drugs have been explored (French and Terlau, 2004). Orientation of μ-conotoxin PIIIA in a sodium channel vestibule is based on the voltage dependence of its binding (McArthur et al., 2011).
One disulfide-rich conotoxin, MrIA, a 13-residue member of the -conotoxin family, inhibits the human norepinephrine transporter (NET) and has potential applications in the treatment of pain. Lovelace et al. (2006) showed that the β-hairpin structure of native MrIA is retained in a synthetic cyclic version, and is biological activity towards NET. The cyclic version has increased resistance to trypsin digestion relative to the native peptide. The increase in enzymatic stability against trypsin may be useful in improving the therapeutic potential of MrIA. The structure of cyclic MrIA (2J15_A) represents a new topology among a growing number of circular disulfide-rich peptides.