1. A Chemoenzymatic Approach To Produce a Cyclic Analogue of the Analgesic Drug MVIIA (Ziconotide).
- Author
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Zhou Y, Harvey PJ, Koehbach J, Chan LY, Jones A, Andersson Å, Vetter I, Durek T, and Craik DJ
- Subjects
- Humans, Analgesics pharmacology, Analgesics therapeutic use, Calcium Channels chemistry, Calcium Channel Blockers pharmacology, omega-Conotoxins pharmacology, omega-Conotoxins therapeutic use, Conotoxins pharmacology
- Abstract
Ziconotide (ω-conotoxin MVIIA) is an approved analgesic for the treatment of chronic pain. 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)-mediated cyclization was used to generate backbone cyclic analogues of MVIIA for the first time. Cyclization using six- to nine-residue linkers did not perturb the overall structure of MVIIA, and the cyclic analogues of MVIIA showed inhibition of voltage-gated calcium channels (Ca
V 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., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)- Published
- 2023
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