biostudies-literatureZhang YNational Health and Medical Research Council AustraliaNSW Cardiovascular Disease Senior Research GrantAustralian Research Councile70017https://www.ebi.ac.uk/biostudies/studies/S-EPMC12010462biostudies-literatureUnknown31(6)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 varyiJournal of peptide science : an official publication of the European Peptide SocietyCyclization of the Analgesic α-Conotoxin Vc1.1 With a Non-Natural Linker: Effects on Structure, Stability, and Bioactivity.PMC12010462APP20145442009564DP200102377CE200100012Craik DJAdams DJZhang YTae HSDurek TfalseCyclization of the Analgesic α-Conotoxin Vc1.1 With a Non-Natural Linker: Effects on Structure, Stability, and Bioactivity.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 varyi2025-01-01T00:00:00Z2025 Jun2025-07-02T03:05:03.612Z2025-07-02T03:05:03.612ZS-EPMC120104624025693510.1002/psc.70017