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Open AccessArticle

Structural and Functional Characterization of Conotoxins from Conus achatinus Targeting NMDAR

State Key Laboratory of NBC Protection for Civilian, Beijing 102205, China
Author to whom correspondence should be addressed.
Mar. Drugs 2020, 18(3), 135;
Received: 23 January 2020 / Revised: 24 February 2020 / Accepted: 24 February 2020 / Published: 26 February 2020
(This article belongs to the Special Issue Cone Snail Venom Peptides, from Treasure Hunt to Drug Leads)
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. View Full-Text
Keywords: conotoxins; N-methyl-D-aspartate receptor; structure-activity relationship; Conus achatinus conotoxins; N-methyl-D-aspartate receptor; structure-activity relationship; Conus achatinus
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Liu, X.; Yao, G.; Wang, K.; Liu, Y.; Wan, X.; Jiang, H. Structural and Functional Characterization of Conotoxins from Conus achatinus Targeting NMDAR. Mar. Drugs 2020, 18, 135.

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