Rationally Designed α-Conotoxin Analogues Maintained Analgesia Activity and Weakened Side Effects

Abstract

A lack of specificity is restricting the further application of conotoxin from Conus bullatus (BuIA). In this study, an analogue library of BuIA was established and virtual screening was used, which identified high α7 nicotinic acetylcholine receptor (nAChR)-selectivity analogues. The analogues were synthesized and tested for their affinity to functional human α7 nAChR and for the regulation of intracellular calcium ion capacity in neurons. Immunofluorescence, flow cytometry, and patch clamp results showed that the analogues maintained their capacity for calcium regulation. The results of the hot-plate model and paclitaxel-induced peripheral neuropathy model indicated that, when compared with natural BuIA, the analgesia activities of the analogues in different models were maintained. To analyze the adverse effects and toxicity of BuIA and its analogues, the tail suspension test, forced swimming test, and open field test were used. The results showed that the safety and toxicity of the analogues were significantly better than BuIA. The analogues of BuIA with an appropriate and rational mutation showed high selectivity and maintained the regulation of Ca2+ capacity in neurons and activities of analgesia, whereas the analogues demonstrated that the adverse effects of natural α-conotoxins could be reduced.

Chinese Medicinal Herb-Derived Carbon Dots for Common Diseases: Efficacies and Potential Mechanisms

“…Cancer pain, acute or chronic pain have emerged as a Gordian knot in medical practice. Prescription opioids remain the first-line treatments for analgesia, but their misuse has escalated rapidly, resulting in a dramatic growth in cases of opioid reliance and overdose deaths ( Brady et al, 2016 ; Liu et al, 2019 ), making it urgent to develop safer analgesic regimens involving nonopioid compounds. The pain relief effect of nanoparticles has gained attention.…”

Historical Perspective of the Characterization of Conotoxins Targeting Voltage-Gated Sodium Channels

“…This work has evolved to include robust computational approaches including molecular dynamics and in silico scanning of potential α-conotoxin analogues (reviewed by [48]); recent work includes [49][50][51][52][53][54]. These and functional investigations have explored α-conotoxin specificity in the characterization of nAChR permutations, and the potential therapeutic use of naturally occurring, synthetic, and mutant α-conotoxins to treat neurodegenerative diseases including Parkinson's Disease [55][56][57][58][59][60], as well as management of peripheral painful neuropathies [51,[61][62][63][64][65][66].…”

Marine Origin Ligands of Nicotinic Receptors: Low Molecular Compounds, Peptides and Proteins for Fundamental Research and Practical Applications

“…Perhaps the analgesic mechanism is even more complex, since the first data on the modulation of G protein-coupled inwardly rectifying potassium (GIRK) channels by these conotoxins via the activation of GABA B receptors have appeared [ 195 ]. Meanwhile, over the past decade, new data have appeared on analgesic activity in various animal pain models for other conopeptides, in particular, for all three isomers of αO-conotoxin GeXIVA [ 100 , 196 , 197 ], αL-conotoxin lt14a [ 198 , 199 ], α-conotoxins AuIB, MII [ 200 ], BuIA and its analogues [ 201 ], and LvIA [ 202 ].…”