A Chemoenzymatic Approach To Produce a Cyclic Analogue of the Analgesic Drug MVIIA (Ziconotide)

Author:

Zhou Yan1ORCID,Harvey Peta J.1ORCID,Koehbach Johannes1ORCID,Chan Lai Yue1ORCID,Jones Alun2ORCID,Andersson Åsa2ORCID,Vetter Irina3ORCID,Durek Thomas1ORCID,Craik David J.1ORCID

Affiliation:

1. ARC Centre of Excellence for Innovations in Peptide and Protein Science Institute for Molecular Bioscience The University of Queensland Brisbane QLD 4072 Australia

2. Institute for Molecular Bioscience The University of Queensland Brisbane QLD 4072 Australia

3. School of Pharmacy Institute for Molecular Bioscience The University of Queensland Brisbane QLD 4072 Australia

Abstract

AbstractZiconotide (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 (CaV2.2) 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.

Funder

National Health and Medical Research Council

Australian Research Council

Publisher

Wiley

Subject

General Chemistry,Catalysis

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