α-Conotoxin Peptidomimetics: Probing the Minimal Binding Motif for Effective Analgesia

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.

Analgesic α-conotoxins modulate GIRK1/2 channels via GABABreceptor activation and reduce neuroexcitability

“…Analgesic α-conotoxins inhibit α9α10 nAChRs directly and HVA calcium (Cav2.2 and Cav2.3) channels via GABA B R activation (Sadeghi et al , 2017; Kennedy et al , 2020). The GABA B R is abundantly expressed in the somatosensory (afferent) nervous system and its role in mitigating mechanical allodynia and chronic visceral hypersensitivity in animal models of neuropathic and visceral pain, respectively, has been demonstrated (Castro et al , 2017; Loeza-Alcocer et al , 2019).…”

“…Several venom-derived peptides have been demonstrated to selectively target neurotransmitter receptors and ion channels in nociceptive pathways. In particular, a number of relatively small disulfide-rich peptides isolated from marine cone snails called conotoxins exhibit anti-nociceptive activity (Knapp et al , 2012; Sadeghi et al , 2017; Hone et al , 2018; Kennedy et al , 2020). ω-Conotoxin MVIIA, which inhibits neuronal high voltage-activated (HVA) N-type (Cav2.2) calcium channels, is the active element of Prialt™ (Ziconotide), an FDA approved drug for the treatment of intractable pain (Wermeling, 2005).…”

Therapeutic Potential of Peptides Derived from Animal Venoms: Current Views and Emerging Drugs for Diabetes

“…86 However, lack of efficacy in phase IIa trials for diabetic peripheral neuropathic pain led to further clinical research with ACV1 being discontinued, but α-conotoxins are still being explored as future drugs for the treatment of neuropathic pain. [87][88][89] In another attempt to exploit a conotoxin with analgesic properties, the χ-conotoxin χ-MrIA, was extracted from the Conus marmoreus. 90 The 13-residue peptide was found to noncompetitively inhibit the norepinephrine transporter (NET) in humans, 91 whereby inhibiting the reuptake of norepinephrine has demonstrated analgesic properties.…”

Cysteine [2,4] Disulfide Bond as a New Modifiable Site of α-Conotoxin TxIB

“…Disulfide bonds are unstable under reducing conditions, so the strategy of disulfide bond engineering has potential value [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. Presently, there are a variety of strategies employed in conotoxin disulfide bond modification, such as disulfide bond replacement by thioether, lactam bond, selenoether, selenylsulfide, 1,2,3-triazole, diselenide and dicarba [ 23 , 24 ]. Disulfide bond replacement by 1,2,3-triazole was studied in conotoxin MrIA and GI.…”

“…Mar. Drugs 2021, 19, x FOR PEER REVIEW 2 of 11 variety of strategies employed in conotoxin disulfide bond modification, such as disulfide bond replacement by thioether, lactam bond, selenoether, selenylsulfide, 1,2,3-triazole, diselenide and dicarba [23,24]. Disulfide bond replacement by 1,2,3-triazole was studied in conotoxin MrIA and GI.…”