Structural and Functional Characterization of Conotoxins from Conus achatinus Targeting NMDAR

Abstract

Conotoxin-Ac1 and its variant conotoxin-Ac1-O6P, were isolated from the venom duct of Conus achatinus, a fish-hunting cone snail species collected in the Sea of Hainan, China. Conotoxin-Ac1 is linear peptide that contain 15 amino acids. In the present study, we synthesized and structurally and functionally characterized conotoxin-Ac1 as well as 19 variants. Electrophysiological results showed that conotoxin-Ac1 inhibited N-methyl-D-aspartate receptor subunit 2B (NR2B) with an IC50 of 8.22 ± 0.022 μM. Further structure-activity studies of conotoxin-Ac demonstrated that polar amino acid residues were important for modulating its active, and the replacement of N1, O9, E10, and S12 by Ala resulted in a significant decrease in potency to NR2B. °Furthermore, conotoxin-Ac1 and conotoxin-Ac1-O6P were tested in hot-plate and tail-flick assays to measure the potential analgesic activity to an acute thermal stimulus in a dose-dependent manner. Subsequently, the analgesic activity of conotoxin-Ac1 mutants was analyzed by the hot-plate method. The results show that N1, Y2, Y3, E10, N11, S12, and T15 play an important role in the analgesic activity of conotoxin-Ac1. N1 and S12 have significant effects on conotoxin-Ac1 in inhibiting NR2B and analgesic activity. In conclusion, we have discovered that conotoxin-Ac1 is an inhibitor of NMDAR and displays antinociceptive activity.

Marine natural products

“…680 The linear 15-residue peptide conotoxin-Ac1 ( C. achatinus ) is a micromolar inhibitor of the N -methyl- d -aspartate receptor subunit 2B and displays analgesic activity. 681 Five new 15- to 16-residue mini-M conotoxins Bn3b–Bn3f were isolated from the venom of Vietnamese collections of the mollusc-hunter C. bandanus and structures assigned by MS/MS and Edman degradation studies. 682 Similar methodology was used to identify the T1-conotoxin Bn5a from the same organism.…”

Chemical Synthesis and Insecticidal Activity Research Based on α-Conotoxins

“…Conotoxin is the shortest nucleic acid-encoded animal neurotoxin peptide found so far, and it is also the short-chain peptide with the highest cysteine density [ 55 ]. Cysteine is one of the sulfur-containing α-amino acids, and its structure contains sulfhydryl groups [ 56 ].…”

Discovery of a New Analgesic Peptide, Leptucin, from the Iranian Scorpion, Hemiscorpius lepturus

“…This assay was performed to investigate the central analgesic effect [ 46 ]. Briefly, the mice were first placed on 55 °C hot plate and pain responses (hind paw withdrawal, licking and/or shaking) were recorded.…”