Self-Assembly Nanostructure of Myristoylated ω-Conotoxin MVIIA Increases the Duration of Efficacy and Reduces Side Effects

Abstract

Chronic pain is one of the most prevalent health problems worldwide. An alternative to suppress or alleviate chronic pain is the use of peptide drugs that block N-type Ca2+ channels (Cav2.2), such as ω-conotoxin MVIIA. Nevertheless, the narrow therapeutic window, severe neurological side effects and low stability associated with peptide MVIIA have restricted its widespread use. Fortunately, self-assembly endows the peptide with high stability and multiple functions, which can effectively control its release to prolong its duration of action. Inspired by this, MVIIA was modified with appropriate fatty acid chains to render it amphiphilic and easier to self-assemble. In this paper, an N-terminal myristoylated MVIIA (Myr-MVIIA, medium carbon chain length) was designed and prepared to undergo self-assembly. The present results indicated that Myr-MVIIA can self-assemble into micelles. Self-assembled micelles formed by Myr-MVIIA at higher concentrations than MVIIA can prolong the duration of the analgesic effect and significantly reduce or even eliminate the side effects of tremor and coordinated motor dysfunction in mice.

Reductive amination of ω-conotoxin MVIIA: synthesis, determination of modification sites, and self-assembly

“…However, there was no significant difference in the improvement of serum stability between single-site and two-site modification. Comparison with previous work showed that both acylated and alkylated peptides self-assembled to form micelles, improving the serum stability of the peptides (Ding et al 2023 ). This work provides a technical basis for the alkyl chain modification of peptide MVIIA, and the assembly of peptides into micelles will also provide a structural basis for its further study.…”

“…In addition, it is shown that alkyl chain length and spatial exclusion between alkyl chains in the hydrophobic core limit the size and shape of nanospheres formed by peptide self-assembly (Muthusivarajan et al 2020 ). Nanostructures formed by peptide self-assembly are believed to be effective in improving peptide stability, increasing resistance to enzymatic degradation, prolonging the half-life of peptide drugs, and reducing drug side effects (Ding et al 2023 ; Zhou et al 2017 ; Gao et al 2023 ). Many approved fatty acid chain modification (similar to alkyl chain modification) drugs are in clinical use, and the fatty acids commonly used for drug modification are mainly myristic acid and palmitic acid.…”

“…Due to the non-site-specific modifications, the peptide modification sites were identified after the reaction using disulfide bond reduction and secondary mass spectrometry methods. Since previous studies showed that myristoylated MVIIA could self-assemble into micelles, which in turn prolonged the duration of peptide potency, increased stability, and reduced side effects of tremor and coordinated motor dysfunction in mice (Ding et al 2023 ), this work also further investigated the self-assembly properties of the alkyl chain modification products obtained by the reductive amination reaction of peptides, and found that the single-site alkyl chain-modified peptide K2-MVIIA and the two-site alkyl chain-modified peptide K2-K4-MVIIA could self-assemble into micelles and improve serum stability. The shape of the two-site modified MVIIA micelles is more irregular than that of the single-site modified MVIIA, presumably due to the effect of the two alkyl chains.…”

“…Alkyl chain modification of peptides has received much attention in recent years (Evans et al 2020 ; Liu et al 2019 ; Yang et al 2023 ), since alkyl chain introduction renders peptides hydrophobic, which can induce peptide self-assembly and lead to the improvement of peptide drug stability (Gao et al 2023 ; Ding et al 2023 ; Yang et al 2023 ). Our previous study showed that self-assembled micelles formed by N-terminal myristoylated MVIIA at high concentrations can prolong the duration of analgesic effect, improve serum stability, and significantly reduce or even eliminate side effects (Ding et al 2023 ). However, the commonly used solid-phase synthesis method for alkyl-modified peptides is time-consuming.…”

A comprehensive review on ziconotide

“…The Borneol (BOR)-modified Liposomes (LIPs) were membrane fused with exosome Microneedles (MNs) in an animal study provided a safe and effective administration of chronic pain treatment by improving the ability of ziconotide across the BBB [ 133 ]. Myristoylated N-terminal ziconotide can undergo self-assembly onto micelles, resulting in extended analgesic effects and a notable reduction in the risk of side effects such as tremors and impaired motor coordination in mice [ 104 ]. Numerous patents have been filed to theoretically modify ziconotide's structure to enhance its ability to cross the BBB, but none of these modifications have been validated in humans or made commercially available [ 128 , 134 ].…”