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| Identifiers | |
|---|---|
3D model (JSmol) | |
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| Properties | |
| C26H43N11O4 | |
| Molar mass | 573.703 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). | |
RPRFamide is a neurotoxin belonging to the conorfamide family of neuropeptides, which can be found in the venom of cone snails.
RPRFamide is a toxin from the carnivorous marine cone snail Conus textile , a predatory species that mainly lives in tropical waters. [1] The venom of marine cone snails contains a diverse variety of toxins, which include conotoxins.
RPRFamide belongs to the family of conotoxins, more specifically to the conorfamide family or RFamide family which are peptides that target neuronal ion channels in their prey. [2]
The sequence for this toxin is identified as RPRF (R = arginine, P = proline, and F = phenylalanine). An amide group (-NH2) is located at the terminal end (C-terminus). The presence of this group is paramount for its biological activity as it enhances its interaction with ion channels. [3]
The short length, the C-terminal Arg–Phe–NH2 (RFa) motif, and the lack of cysteines clearly distinguishes these peptides from conotoxins and categorises them as cono-RFamides. [3]
Two main molecular targets have been discovered for RPRFamide. Firstly, it targets the acid sensing ion channel 3 (ASIC3), involved in the pain pathway. Secondly, it can target and inhibit nicotinic acetylcholine receptors (nAChRs), specifically the alpha-7 subtype. [3]
The RPRFamide peptide modulates ASIC3, a proton-gated ion channel that is sensitive to acidic conditions and involved in pain perception. This channel is a proton-gated sodium channel involved in nociception in response to acidic environments in a tissue, such as muscle fatigue. [4] The toxin enhances ASIC3 currents, leading to increased pain signalling, particularly in response to acidic stimuli. This explains why RPRFamide can induce pain, particularly muscle pain, through the activation of ASIC3 channels. [5] The peptide delays the desensitization of ASIC3 channels, keeping them open longer and allowing sustained ion flow, which increases sensitivity to pain stimuli and prolongs the nociceptive effect. [4]
Studies show that injecting cono-RFamide into mice muscle leads to increased acid induced pain. [3] [5] Additionally, studies showed that RPRFamide causes an increase in excitability of dorsal root ganglion (DRG) neurons. [5]
The RPRFamide also modulates nACh receptors by inhibiting them, specifically the alpha-7 and muscle-type nAChRs. These receptors are ligand-gated ion channels that mediate fast synaptic transmission in the nervous system and are involved in neuromuscular function. [3] The toxin's inhibitory effect prevents the influx of ions that would normally result from acetylcholine binding, disrupting neurotransmission and impairing muscle contraction, depending on the receptor subtype. [3]
The toxicity of RPRFamide has yet to be assessed in humans. However, available literature suggests that ASIC3 channels are expressed in muscle pain receptors, leading to extreme, long-lasting pain when injected into muscle tissue in mice, particularly when administered with an acidic solution. [5]
Currently, no available literature describes a method to counteract the neurotoxic activity of RPRFamide.
The therapeutic potential of RPRFamide has yet to be fully assessed. Some authors have discussed the neurotoxin's modulation of ASIC3 and nAChRs receptors, suggesting that further research could explore its role in pain modulation, including potential treatments for chronic pain. [3] [4]
An acetylcholine receptor or a cholinergic receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.
Neurotoxins are toxins that are destructive to nerve tissue. Neurotoxins are an extensive class of exogenous chemical neurological insults that can adversely affect function in both developing and mature nervous tissue. The term can also be used to classify endogenous compounds, which, when abnormally contacted, can prove neurologically toxic. Though neurotoxins are often neurologically destructive, their ability to specifically target neural components is important in the study of nervous systems. Common examples of neurotoxins include lead, ethanol, glutamate, nitric oxide, botulinum toxin, tetanus toxin, and tetrodotoxin. Some substances such as nitric oxide and glutamate are in fact essential for proper function of the body and only exert neurotoxic effects at excessive concentrations.
A neuromuscular junction is a chemical synapse between a motor neuron and a muscle fiber.
Ziconotide, sold under the brand name Prialt, also called intrathecal ziconotide (ITZ) because of its administration route, is an atypical analgesic agent for the amelioration of severe and chronic pain. Derived from Conus magus, a cone snail, it is the synthetic form of an ω-conotoxin peptide.
A conotoxin is one of a group of neurotoxic peptides isolated from the venom of the marine cone snail, genus Conus.
Tropidolaemus wagleri, more commonly known as Wagler's pit viper, is a species of venomous snake, a pit viper in the subfamily Crotalinae of the family Viperidae. The species is endemic to Southeast Asia. There are no subspecies that are recognized as being valid. It is sometimes referred to as the temple viper because of its abundance around the Temple of the Azure Cloud in Malaysia.
α-Bungarotoxin is one of the bungarotoxins, components of the venom of the elapid Taiwanese banded krait snake. It is a type of α-neurotoxin, a neurotoxic protein that is known to bind competitively and in a relatively irreversible manner to the nicotinic acetylcholine receptor found at the neuromuscular junction, causing paralysis, respiratory failure, and death in the victim. It has also been shown to play an antagonistic role in the binding of the α7 nicotinic acetylcholine receptor in the brain, and as such has numerous applications in neuroscience research.
The contryphans are a family of peptides that are active constituents of the potent venom produced by cone snail. The two amino acid cysteine residues in contryphans are linked by a disulfide bond. In addition, contryphans undergo an unusual degree of post-translational modification including epimerization of leucine and tryptophan, tryptophan bromination, amidation of the C-terminus, and proline hydroxylation. In the broader scheme of genetic conotoxin classification, contryphans are members of "Conotoxin Superfamily O2."
Bungarotoxins are toxins found in the venom of snakes and kraits. Bites from these animals can result in severe symptoms including bleeding or hemorrhage, paralysis and tissue damage that can result in amputation. The paralytic effects of venom are particularly dangerous as they can impair breathing. These symptoms are the result of bungarotoxin presence in the venom. In actuality, venom contains several distinct bungarotoxins, each varying in which receptors they act on and how powerful they are.
α-Cobratoxin is a substance of the venom of certain Naja cobras. It is a nicotinic acetylcholine receptor (nAChR) antagonist which causes paralysis by preventing the binding of acetylcholine to the nAChR.
Philanthotoxins are components of the venom of the Egyptian solitary wasp Philanthus triangulum, commonly known as the European beewolf. Philanthotoxins are polyamine toxins, a group of toxins isolated from the venom of wasps and spiders which immediately but reversibly paralyze their prey. δ-philanthotoxin, also known as PhTX-433, is the most active philanthotoxin that can be refined from the venom. PhTX-433 functions by non-selectively blocking excitatory neurotransmitter ion channels, including nicotinic acetylcholine receptors (nAChRs) and ionotropic glutamate receptors (iGluRs). Synthetic analogues, including PhTX-343 and PhTX-12, have been developed to improve selectivity. While the IC50 values of philanthotoxins varies between analogues and receptor subunit composition, the IC50 value of PhTX-433 at the iGluR AMPA receptor naturally expressed in locust leg muscle is 18 μM and the IC50 value at rat nAChRs is 1 μM.
Psalmotoxin (PcTx1) is a spider toxin from the venom of the Trinidad tarantula Psalmopoeus cambridgei. It selectively blocks Acid Sensing Ion Channel 1-a (ASIC1a), which is a proton-gated sodium channel.
Conus victoriae, common name the Queen Victoria cone, is a species of sea snail, a marine gastropod mollusk in the family Conidae, the cone snails and their allies.
Conantokins are a small family of helical peptides that are derived from the venom of predatory marine snails of the genus Conus. Conantokins act as potent and specific antagonists of the N-methyl-D-aspartate receptor (NMDAR). They are the only naturally-derived peptides to do so. The subtypes of conantokins exhibit a surprising variability of selectivity across the NMDAR subunits, and are therefore uniquely useful in developing subunit-specific pharmacological probes.
α-Neurotoxins are a group of neurotoxic peptides found in the venom of snakes in the families Elapidae and Hydrophiidae. They can cause paralysis, respiratory failure, and death. Members of the three-finger toxin protein family, they are antagonists of post-synaptic nicotinic acetylcholine receptors (nAChRs) in the neuromuscular synapse that bind competitively and irreversibly, preventing synaptic acetylcholine (ACh) from opening the ion channel. Over 100 α-neurotoxins have been identified and sequenced.
ConoServer is a database of toxins that are expressed by the predatory sea snails in the family Conidae, the cone snails. These toxins are known as conotoxins or conopeptides. The toxins are of importance to medical research. A notable feature of these peptides is their high specificity and affinity towards human ion channels, receptors and transporters of the nervous system. This makes conopeptides an interesting resource for the physiological studies of neuroreceptors and promising drug leads.
Huwentoxins (HWTX) are a group of neurotoxic peptides found in the venom of the Chinese bird spider Haplopelma schmidti. The species was formerly known as Haplopelma huwenum, Ornithoctonus huwena and Selenocosmia huwena. While structural similarity can be found among several of these toxins, HWTX as a group possess high functional diversity.
Covalitoxin-II is a peptide toxin that is produced by the spider Coremiocnemis validus. It can induce excitatory, non-lethal behavioral symptoms like quivering and jerking in crickets.
κ-Bungarotoxin is a protein neurotoxin of the bungarotoxin family that is found in the venom of the many-banded krait, a snake found in Taiwan. κ-Bungarotoxin is a high affinity antagonist of nicotinic acetylcholine receptors (nAChRs), particularly of CHRNA3; it causes a post-synaptic blockade of neurotransmission. Although there is significant variability in the clinical effects of snake bites, neuromuscular paralysis and respiratory failure are associated with krait bites.
Three-finger toxins are a protein superfamily of small toxin proteins found in the venom of snakes. Three-finger toxins are in turn members of a larger superfamily of three-finger protein domains which includes non-toxic proteins that share a similar protein fold. The group is named for its common structure consisting of three beta strand loops connected to a central core containing four conserved disulfide bonds. The 3FP protein domain has no enzymatic activity and is typically between 60-74 amino acid residues long. Despite their conserved structure, three-finger toxin proteins have a wide range of pharmacological effects. Most members of the family are neurotoxins that act on cholinergic intercellular signaling; the alpha-neurotoxin family interacts with muscle nicotinic acetylcholine receptors (nAChRs), the kappa-bungarotoxin family with neuronal nAChRs, and muscarinic toxins with muscarinic acetylcholine receptors (mAChRs).