Structure and Activity Studies of Disulfide-Deficient Analogues of αO-Conotoxin GeXIVA

αO-conotoxin
GeXIVA from Conus generalis is a potent antagonist
of the α9α10 nAChR and analgesic
in animal models of pain.
This peptide has two disulfide bond cross-links, and the bead and
ribbon isomers have similar inhibitory activity against α9α10
nAChRs. We synthesized 12 disulfide-deficient analogues of bead GeXIVA,
and all remained potent inhibitors of α9α10 nAChR. The
most potent disulfide-deficient analogue displayed IC50 values of 6 and 33 nM at rat and human α9α10 nAChRs,
respectively, representing less than a 2-fold increase compared with
bead GeXIVA. The disulfide-deficient analogs and parent peptides also
do not have a well-defined structure according to NMR spectroscopy.
Molecular simulations suggest that the disulfide bonds and termini
of GeXIVA do not establish stable interactions with the receptor.
Overall, this study proposes that the structure of the analgesic peptide
GeXIVA could be simplified through disulfide bond deletions and potentially
termini truncations.