Cyclization of the Analgesic α‐Conotoxin Vc1.1 With a Non‐Natural Linker: Effects on Structure, Stability, and Bioactivity
Year: 2025
Type: article
Abstract: α-Conotoxin Vc1.1 is a disulfide-rich peptide and a promising drug candidate for treating neuropathic and chronic pain. Backbone cyclization was applied to enhance its drug-like properties, resulting in improved serum stability and oral bioavailability. However, this modification also adversely affected its stability and activity in simulated intestinal fluid (SIF). To address these adverse effects, we explored the use of polyethylene glycol (PEG) linkers as substitutes for peptide backbone cyclization linkers. PEG linkers are smaller, more flexible, and more stable than peptide linkers. Furthermore, previous studies have demonstrated that PEG backbone linkers can enhance the activity of conotoxins. In this study, we synthesized four PEG-backboned cyclic Vc1.1 (cVc1.1) analogues with varying lengths of PEG linkers and used a chemo-enzymatic method to cyclize these analogues. Their structure, stability, and activity were subsequently evaluated. Although the results revealed that PEG linkers preserved the SIF stability and activity of cVc1.1, they highlighted the crucial role of the peptide's helical structure in maintaining its stability and activity. Additionally, this work introduces a novel approach for synthesizing cyclic conotoxins.
Source: Journal of Peptide Science
DOI: 10.1002/psc.70017
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,030
Awards: ARC Centre of Excellence for Innovations in Peptide and Protein Science, Toxins from Down Under: Novel tools to understand and modulate ion channels, Advancing peptide-based drug design, G5572172683, Novel long-acting and orally delivered conotoxin-based peptides with both analgesic efficacy and disease modifying potential.
OpenAlex ID: W4409622988