G-Protein Coupled Receptors Targeted by Analgesic Venom Peptides

Abstract

Chronic pain is a complex and debilitating condition associated with a large personal and socioeconomic burden. Current pharmacological approaches to treating chronic pain such as opioids, antidepressants and anticonvulsants exhibit limited efficacy in many patients and are associated with dose-limiting side effects that hinder their clinical use. Therefore, improved strategies for the pharmacological treatment of pathological pain are urgently needed. G-protein coupled receptors (GPCRs) are ubiquitously expressed on the surface of cells and act to transduce extracellular signals and regulate physiological processes. In the context of pain, numerous and diverse families of GPCRs expressed in pain pathways regulate most aspects of physiological and pathological pain and are thus implicated as potential targets for therapy of chronic pain. In the search for novel compounds that produce analgesia via GPCR modulation, animal venoms offer an enormous and virtually untapped source of potent and selective peptide molecules. While many venom peptides target voltage-gated and ligand-gated ion channels to inhibit neuronal excitability and blunt synaptic transmission of pain signals, only a small proportion are known to interact with GPCRs. Of these, only a few have shown analgesic potential in vivo. Here we review the current state of knowledge regarding venom peptides that target GPCRs to produce analgesia, and their development as therapeutic compounds.

Targeting Cannabinoid Receptors: Current Status and Prospects of Natural Products

“…However, the detailed action mechanisms of these peptides on opioid or cannabinoid receptors remain unknown. In the search for novel compounds that produce analgesia via GPCR modulation, animal venoms offer an enormous and mostly untapped source of potent and selective peptide molecules [ 174 ]. Another example related to this is that the GABA B receptor (GABA B R) appears to play a critical role in analgesia of α-conotoxin Vc1.1 in rodent models of pain, while the precise nature of α-conotoxin Vc1.1 binding to GABA B R is currently unknown [ 174 ].…”

“…In the search for novel compounds that produce analgesia via GPCR modulation, animal venoms offer an enormous and mostly untapped source of potent and selective peptide molecules [ 174 ]. Another example related to this is that the GABA B receptor (GABA B R) appears to play a critical role in analgesia of α-conotoxin Vc1.1 in rodent models of pain, while the precise nature of α-conotoxin Vc1.1 binding to GABA B R is currently unknown [ 174 ]. Additionally, it is evident that cannabinoid receptors are one of the primary GPCR targets of natural products based [ 37 ].…”

Identification of Conomarphin Variants in the Conus eburneus Venom and the Effect of Sequence and PTM Variations on Conomarphin Conformations

“…The venom of marine cone snails is a goldmine for neuroactive peptides known as conopeptides. Current estimates report that cone snail venom consists of hundreds to thousands of conopeptides that act on a wide range of pharmacological targets such as ion channels and G protein-coupled receptors [ 1 , 2 , 3 ]. For this reason, these conopeptides are being explored as lead compounds for drug discovery and development [ 3 , 4 , 5 , 6 ].…”

“…Current estimates report that cone snail venom consists of hundreds to thousands of conopeptides that act on a wide range of pharmacological targets such as ion channels and G protein-coupled receptors [ 1 , 2 , 3 ]. For this reason, these conopeptides are being explored as lead compounds for drug discovery and development [ 3 , 4 , 5 , 6 ]. Bioassay-guided fractionation of venom peptides has been very successful in identifying these bioactive peptides, and has paved the way for basic biochemical studies and the elucidation of molecular mechanisms of action of select peptide targets [ 5 , 6 , 7 , 8 , 9 ].…”

Discovery Methodology of Novel Conotoxins from Conus Species

“…Early studies have confirmed that these bioactive venoms are a cocktail of neuroactive peptides, termed conopeptides or conotoxins, which can cause paralysis, shudder, and even death of the prey within seconds [ 1 , 5 ]. Subsequent research have revealed that conopeptides are able to selectively modulate voltage-gated ion channels [ 7 ] ( Table 1 ), including sodium channels [ 8 , 9 ], potassium channels [ 10 ], and calcium channels [ 11 , 12 ], as well as ligand-gated ion channels ( Table 1 ), such as nAChRs [ 13 , 14 , 15 ], serotonin receptor [ 16 ], NMDA receptor [ 17 ], GABA receptor [ 18 ], GPCRs [ 19 ] (α 1 -adrenoceptors [ 20 , 21 ], vasopressin receptor [ 22 ], neurotensin receptor [ 23 ]), and neurotransmitter transporters (noradrenaline transporter [ 21 , 24 ]), which are key targets for chronic diseases, like neuralgia [ 8 , 25 , 26 ], addiction [ 27 ], epilepsy [ 17 , 28 ], cancer [ 29 ], heart disease [ 30 , 31 ], and so on [ 32 , 33 , 34 ].…”