α-Conotoxin Vc1.1 (Vc1.1) is a 16 amino acid synthetic version of a conopeptide, which was first discovered from a PCR screen of cDNA from the venom ducts of the tropical marine snail, Conus victoriae¹. Vc1.1 adopts the archetypal three-dimensional structure of a-conotoxins, which consists of a helical region stabilized by two disulfide bonds. The α-conotoxin family members are defined, in part, by their pharmacological targets, the nicotinic acetylcholine receptors (nAChRs). Vc1.1 is a neuronal nAChR antagonist that displays selectivity for the α9α10 subtype². A subset of α-conotoxins have been shown to inhibit high-voltage-activated (HVA) calcium channel currents via activation of the γ-aminobutyric acid (GABA) receptor B (GABA_BR). GABA_BRs are G-protein-coupled receptors (GPCRs) for GABA, the main inhibitory neurotransmitter in the brain. GABA_BRs are promising targets for the treatment of various neurological and psychiatric disorders, including pain, depression, and drug addiction. Vc1.1 was the first α-conotoxin shown to inhibit HVA calcium channels (Ca_V2.2 and Ca_V2.3) via GABA_BR activation^3,4.

Vc1.1 alleviates neuropathic pain in three human neuropathic pain rat models and accelerates the functional recovery of injured neurons⁵. This toxin has been tested in human clinical trials for the treatment of neuropathic pain, where it exhibited both clean safety and side effect profiles. In addition to its antinociceptive and antihyperalgesic actions in neuropathic pain models, Vc1.1 inhibits human DRG neurons via activation of the GABA_BR, which are the primary transducers at the start of the pain processing pathway⁶.