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Backbone cyclization was applied to enhance its drug\u2010like 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\u2010backboned cyclic Vc1.1 (cVc1.1) analogues with varying lengths of PEG linkers and used a chemo\u2010enzymatic 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.<\/jats:p>","DOI":"10.1002\/psc.70017","type":"journal-article","created":{"date-parts":[[2025,4,21]],"date-time":"2025-04-21T10:25:41Z","timestamp":1745231141000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Cyclization of the Analgesic \u03b1\u2010Conotoxin Vc1.1 With a Non\u2010Natural Linker: Effects on Structure, Stability, and Bioactivity"],"prefix":"10.1002","volume":"31","author":[{"given":"Yuhui","family":"Zhang","sequence":"first","affiliation":[{"name":"Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science The University of Queensland  Brisbane QLD 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