Discovery and optimisation of conotoxin Vc1.1 and analogues with analgesic properties

Majbrit Frøsig-Jørgensen; Jing Ji; Declan M. Gorman; Meng-Wei Kan; David J. Craik

doi:10.1071/CH23155

RESEARCH ARTICLE (Open Access)

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Discovery and optimisation of conotoxin Vc1.1 and analogues with analgesic properties

Majbrit Frøsig-Jørgensen

^A , Jing Ji

^A , Declan M. Gorman

^A , Meng-Wei Kan

^A and David J. Craik

^A ^*

+ Author Affiliations

- Author Affiliations

^A Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Qld 4072, Australia.

^* Correspondence to: d.craik@imb.uq.edu.au

Handling Editor: Curt Wentrup

Australian Journal of Chemistry 76(10) 655-670 https://doi.org/10.1071/CH23155
Submitted: 16 August 2023 Accepted: 15 September 2023 Published: 6 October 2023

© 2023 The Author(s) (or their employer(s)). Published by CSIRO Publishing. This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND)

Abstract

A specimen of the marine cone snail Conus victoriae collected from a beach in Broome, Western Australia, by a group from The University of Melbourne led to the discovery of the α-conotoxin Vc1.1, which was found to have analgesic activity in rodents. The discovery of this venom-derived peptide led to a series of structural, mechanistic and pharmacological studies directed towards the development of a new analgesic for neuropathic pain by groups in Australia and internationally. Solid-phase peptide synthesis played an important role in developing structure–activity relationships. Studies in a rat model of neuropathic pain showed that a cyclic analogue of the peptide, cVc1.1, had comparable analgesic activity with that of gabapentin, one of the foremost clinically used drugs for neuropathic pain, with cVc1.1 delivered orally at a 120-fold lower dose than gabapentin. Originally, Vc1.1 was believed to act primarily through nicotinic acetylcholine receptors, but evidence for a mechanism mediated through γ-aminobutyric acid B (GABA_B) receptors later emerged. Efforts to optimise the binding and pharmacological properties of analogues of Vc1.1 revealed that the affinity towards either receptor can be modulated by sequence mutations, disulfide bond modifications and backbone cyclisation. This Account describes the discovery, structure, chemistry and pharmacology of Vc1.1, with a focus on studies carried out in Australian laboratories.

Keywords: conotoxin, drug design, drug development, drug discovery, GABA_BR, gamma-aminobutyric acid receptor, nAChR, nicotinic acetylcholine receptors, pain, peptide, pharmacology, venom.

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