bi8b00803_si_001.pdf (214.45 kB)
Structure–Activity Analysis of N‑Type Calcium Channel Inhibitor SO‑3
journal contribution
posted on 2018-10-03, 00:00 authored by Minxing Dong, Fei Wang, Zhenzhen Yan, Shuo Yu, Juanjuan Wei, Qiaoling Wu, Zhuguo Liu, Yifei Tang, Jiuping Ding, Qiuyun DaiAs
an ω-conopeptide originally discovered from Conus
striatus, SO-3 contains 25 amino acid residues and three
disulfide bridges. Our previous study has shown that this peptide
possesses potent analgesic activity in rodent pain models (mouse and
rat), and it specifically inhibits an N-type calcium ion channel (Cav2.2).
In the study presented here, we investigated the key amino acid residues
for their inhibitory activity against Cav2.2 expressed in HEK 293
cells and analgesic activity in mice. To improve the inhibitory activity
of SO-3, we also evaluated the effects of some amino acid residues
derived from the corresponding residues of ω-peptide MVIIA,
CVID, or GVIA. Our data reveal that Lys6, Ile11, and Asn14 are the
important functional amino acid residues for SO-3. The replacement
of some amino acid residues of SO-3 in loop 1 with the corresponding
residues of CVID and GVIA improved the inhibitory activity of SO-3.
The binding mode of Cav2.2 with SO-3 amino acids in loop 1 and loop
2 may be somewhat different from that of MVIIA. This study expanded
our knowledge of the structure–activity relationship of ω-peptides
and provided a new strategy for improving the potency of Cav2.2 inhibitors.