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

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 (GABAB) 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.

Celebrating RACI and Academy of Science awards 2022–23

“…Backbone cyclisation of the conotoxin proved to be particularly effective in improving potency and pharmacological properties of the peptide, improve biological stability and reduce proteolytic degradation, and the backbone cyclisation also improved the oral bioavailability. 1 Yu Heng Lau (The University of Sydney), the winner of an Early Career Travel Bursary, is the author of an account on the supramolecular chemistry of protein cages and viruses. Examples of protein cages include the outer capsid shells of viruses and simple organellelike structures in bacteria that house enzymes in the interior.…”