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However, the need for intrathecal administration and adverse effects have limited its widespread application. Backbone cyclization is one way to improve the pharmaceutical properties of conopeptides, but so far chemical synthesis alone has been unable to produce correctly folded and backbone cyclic analogues of MVIIA. In this study, an asparaginyl endopeptidase (AEP)\u2010mediated cyclization was used to generate backbone cyclic analogues of MVIIA for the first time. Cyclization using six\u2010 to nine\u2010residue linkers did not perturb the overall structure of MVIIA, and the cyclic analogues of MVIIA showed inhibition of voltage\u2010gated calcium channels (Ca<jats:sub>V<\/jats:sub>2.2) and substantially improved stability in human serum and stimulated intestinal fluid. Our study reveals that AEP transpeptidases are capable of cyclizing structurally complex peptides that chemical synthesis cannot achieve and paves the way for further improving the therapeutic value of conotoxins.<\/jats:p>","DOI":"10.1002\/anie.202302812","type":"journal-article","created":{"date-parts":[[2023,5,6]],"date-time":"2023-05-06T09:40:14Z","timestamp":1683366014000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["A Chemoenzymatic Approach To Produce a Cyclic Analogue of the Analgesic Drug MVIIA (Ziconotide)"],"prefix":"10.1002","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0086-9884","authenticated-orcid":false,"given":"Yan","family":"Zhou","sequence":"first","affiliation":[{"name":"ARC Centre of Excellence for Innovations in Peptide and Protein Science Institute for Molecular Bioscience The University of Queensland  Brisbane QLD 4072 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