Backbone cyclization turns a venom peptide into a stable and equipotent ligand at both muscle and neuronal nicotinic receptors

Giribaldi, Julien, Haufe, Yves, Evans, Evans R.J., Amar, Muriel, Durner, Anna, Schmidt, Casey, Faucherre, Adèle, Moha Ou Maati, Hamid, Enjalbal, Christine, Molgó, Jordi, Servent, Denis, Wilson, David T., Daly, Norelle L., and Nicke, Annette (2020) Backbone cyclization turns a venom peptide into a stable and equipotent ligand at both muscle and neuronal nicotinic receptors. Journal of Medicinal Chemistry, 63 (21). pp. 12682-12692.

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Venom peptides are promising drug leads, but their therapeutic use is often limited by stability and bioavailability issues. In this study, we designed cyclic analogues of α-conotoxin CIA, a potent muscle nicotinic acetylcholine receptor (nAChR) blocker with a significantly lower affinity at the neuronal α3β2 subtype. Remarkably, all analogues retained the low nanomolar activity of native CIA toward muscle-type nAChRs but showed greatly improved resistance to degradation in human serum and, surprisingly, displayed up to 52-fold higher potency for the α3β2 neuronal nAChR subtype (IC50 1.3 nM). Comparison of nuclear magnetic resonance-derived structures revealed some differences that might explain the gain of potency at α3β2 nAChRs. All peptides were highly paralytic when injected into adult zebrafish and bath-applied to zebrafish larvae, suggesting barrier-crossing capabilities and efficient uptake. Finally, these cyclic CIA analogues were shown to be unique pharmacological tools to investigate the contribution of the presynaptic α3β2 nAChR subtype to the train-of-four fade.

Item ID: 66234
Item Type: Article (Research - C1)
ISSN: 1520-4804
Copyright Information: © 2020 American Chemical Society
Funders: French Ministry of Higher Education, Research, and Innovation, French National Research Agency (ANR), DFG German Research Foundation (DFG)
Projects and Grants: ANR-16-CE34-0002, DFG Research Training Group GRK2338, P01
Date Deposited: 24 Feb 2021 23:00
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3205 Medical biochemistry and metabolomics > 320506 Medical biochemistry - proteins and peptides (incl. medical proteomics) @ 100%
SEO Codes: 28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280102 Expanding knowledge in the biological sciences @ 100%
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