Abstract
Several analgesic α-conotoxins have been isolated from marine cone snails. Structural modification of native peptides has provided potent and selective analogues for two of its known biological targets—nicotinic acetylcholine and γ-aminobutyric acid (GABA) G protein-coupled (GABAB) receptors. Both of these molecular targets are implicated in pain pathways. Despite their small size, an incomplete understanding of the structure-activity relationship of α-conotoxins at each of these targets has hampered the development of therapeutic leads. This review scrutinises the N-terminal domain of the α-conotoxin family of peptides, a region defined by an invariant disulfide bridge, a turn-inducing proline residue and multiple polar sidechain residues, and focusses on structural features that provide analgesia through inhibition of high-voltage-activated Ca2+ channels. Elucidating the bioactive conformation of this region of these peptides may hold the key to discovering potent drugs for the unmet management of debilitating chronic pain associated with a wide range of medical conditions.
Highlights
Venomous marine cone snails of the genus Conus, estimated to contain more than 700 species, possess a unique mixture of pharmacologically-active peptides [1,2,3,4]
Previously-described analgesic Loop I dicarba Vc1.1 and RgIA analogues were selective for the GABAB receptor and devoid of α9α10 nicotinic acetylcholine receptors (nAChRs) activity, further suggesting that a Loop I-contained epitope is solely capable of providing potent in vivo analgesia [84,106]
70 α-conotoxin sequences have been reported in the literature and more than half of these peptides share a highly-conserved N-terminal sequence tethered by a cystine bridge
Summary
Venomous marine cone snails of the genus Conus, estimated to contain more than 700 species, possess a unique mixture of pharmacologically-active peptides [1,2,3,4]. In combination with a conserved turn-inducing proline residue, the interlocked disulfide bridge framework stabilises the three-dimensional architecture into two clear domains—Loop I (N-terminus to residue 8) and Loop II (residue 9 to the C-terminus) This stabilised structure results in peptides that typically display high efficacy, potency and selectivity for their receptor targets, making them prime candidates for drug development [9,10]. At the level of the dorsal horn, GABAB receptors are located on the presynaptic terminals of the primary afferents arising from the DRG and on cell bodies and processes of interneurones in laminae I, II and III, the latter involved in processing tactile sensory information [27] They are located on presynaptic terminals originating from descending inputs from higher centres. The market, several promising analgesic α-conotoxin lead sequences have been identified (Table 1)
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