Conotoxins,
disulfide-rich
peptides from the
venom of cone snails, have created much excitement over recent years due to their potency and specificity for
ion channels and their therapeutic potential. One recently identified
conotoxin, MrIA, a 13-residue member of the chi-
conotoxin family, inhibits the human
norepinephrine transporter (NET) and has potential applications in the treatment of
pain. In the current study, we show that the beta-hairpin structure of native MrIA is retained in a synthetic cyclic version, as is
biological activity at the NET. Furthermore, the cyclic version has increased resistance to
trypsin digestion relative to the native
peptide, an intriguing result because the cleavage site for the
trypsin is not close to the cyclization site. The use of
peptides as drugs is generally hampered by susceptibility to proteolysis, and so, the increase in enzymatic stability against
trypsin observed in the current study may be useful in improving the therapeutic potential of MrIA. Furthermore, the structure reported here for cyclic MrIA represents a new topology among a growing number of circular
disulfide-rich
peptides.