Properties and Pharmacology of Scorpion Toxins and Their Biotechnological Potential in Agriculture and Medicine
Abstract
1. Introduction
2. Scorpion Venoms: An Overview of Composition and Diversity
3. Evolving Paradigms in Scorpion Toxin Classification
3.1. General Classification of Toxin Families
3.2. General Organization of Scorpion Peptide Genes
3.3. Scorpion Disulfide-Bridged Peptides (DBPs)
3.3.1. Cystine-Stabilized α/β (CSα/β) Scaffold
Long-Chain Scorpion Toxins (Protein Family PF14866)
Short-Chain Scorpion Toxins (Protein Family PF00451)
KTx Subfamily | Length (Amino Acids) | Disulfide Bridges | Key Structural Features | Primary Target/Function | Noteworthy Characteristics | References |
---|---|---|---|---|---|---|
General Short KTxs | 23–64 | 3–4 | - | K+ channel blockade | - | [101] |
α-KTx | 23–42 | 3 or 4 | CS α/β motif (α-helix + β-sheet) | K+ channel blockade | Largest subgroup of short scorpion toxins. | [63,120] |
β-KTx | 50–75 | - | CS α/β motif | K+ channel blockade | Comprises longer chain peptides within the short toxin family. | [63,110] |
γ-KTx | - | - | CS α/β motif | Human Ether-à-go-go-Related Gene (hERG) channels | Found in the genera Centruroides, Mesobuthus, and Buthus. | [112,121] |
κ-KTx | - | 2 | Two parallel short α-helices connected by a β-turn | K+ channel blockade | Interaction with K+ channels similar to α-KTx, despite structural difference. | [115] |
δ-KTx | 59–70 | 3 | Kunitz-type structural fold (double-stranded antiparallel β-sheet flanked by α-helix) | K+ channel blockade; Serine protease inhibition | Exerts antiprotease and K+ channel-blocking properties. | [68] |
λ-KTx | 29–49 | 3 | Inhibitor cystine knot (ICK) motif (triple-stranded antiparallel β-sheet) | - | Related to calcins | [122,123] |
ε-KTx | - | 4 | ICK motif (unique pattern) | - | Only two members (Ts11 and Ts12 from T. serrulatus venom); Ts11 shows <50% identity with other KTxs. | [23,107] |
3.3.2. Calcium Channel-Modulating Peptides (Calcins) (Protein Family PF08099)
3.3.3. Chloride Channel Toxins (Protein Subfamily PS51200)
Species | Toxin Name | Molecular Mass (kDa) | Target(s) | Biological Activity | References |
---|---|---|---|---|---|
Leiurus quinquestriatus quintestriatus | Venom (peptide(s) not identified) | - | Slow conductance Cl− channels (ClC) | Venom caused voltage-dependent reversible blockade of small conductance Cl− channels from embryonic rat brain growth cones (200 μg/mL) and anion channels from rat colonic epithelial cells (enterocytes) (100 and 400 μg/mL) reconstituted in artificial membranes (stoichiometry of one toxin molecule per channel). Channels blocked in open state. Large conductance Cl− channels of blood cells (predominantly platelets and white blood cells) were unaffected by venom (200 μg/mL). Specific Cl− channel type not identified in these studies. | [143,144] |
Chlorotoxin (ClTx) | ~5 (4.07) | Slow conductance Cl− channels (ClC) | Purified toxin (ClTx) reproduced the venom activity initially reported by DeBin and Strichartz [143] and blocked CIC with a KD of ~600 nM. ClTx caused progressive, reversible paralysis (recovery depended on venom dose) in crayfish and cockroaches, and accounted for ~4.3% of the venom protein content. Blockade seen only when ClTx was applied to the cytoplasmic surface. A later study reported that ClTx applied extracellularly did not block volume-regulated, CFTR (cAMP-regulated) and glioma-specific Cl− channels [147]. | [144,147] | |
Ca2+-regulated Cl− channels | Ca2+-regulated Cl− channels in astrocytes were potently blocked by ClTx [146], whereas similar channels in a human colon carcinoma (T84) cell line were not blocked by ClTx [147]. | [146,147] | |||
Leiurus quinquestriatus hebraeus | Venom (peptide(s) not identified) | ---- | ClC-2 Cl− channels | A peptide-enriched fraction of venom (obtained by filtering through 10 kDa-cutoff filters) caused concentration-dependent, progressive, reversible blockade of rabbit CIC-2 (but not Torpedo CIC-0 or human CIC-1) channels when applied extracellularly. Inhibition was unaffected by boiling the venom fraction, but was prevented by incubation with trypsin, indicating involvement of a heat-stable peptide. Blockade produced by modulating the channel gating mechanism (slower activation, but unaltered deactivation). Purified ClTx from L. q. quinquestriatus was inactive on CIC-2 channels. | [145] |
GaTX2 (Gating modifier of anion channels 2) | 3.2 | ClC-2 Cl− channels | A continuation of the investigation reported in [145] identified a toxin with three disulfide bonds and a sequence unrelated to ClTx but identical to previously identified leiuropeptide II from this same venom. Structurally related to toxins that inhibit K+ channels (apamin-sensitive K+ channels, Ca2+-activated K+ channels and Kv1.2 channels). Causes voltage-dependent blockade of ClC-2 channels with an apparent KD of ~20 pM. Slows channel activation but does not block open channels. No blockade of CIC-1, CIC-3 and CIC-4 channels or transporters, nor of CFTR (when applied extracellularly or intracellularly). No effect on GABAC receptors when applied to the extracellular surface, or when applied to the cytosolic side of endogenous Ca2+-activated chloride Cl− channels. No effect on Kv1.2 channels. | [154] | |
Venom (peptide(s) not identified) | ---- | Cystic fibrosis transmembrane conductance regulator (CFTR) | Initial experiments showed that venom reversibly inhibited the CFTR channel in a voltage-dependent manner via a pore-block mechanism. Rapid, all-or-none blockade involving high affinity interaction with the nucleotide binding site of the channel in an interburst closed state, with a reduction in channel burst duration and open probability. No effect on ATP-dependent macroscopic opening rate. Only active when applied to the cytoplasmic side of phosphorylated channels. Activity was unaffected by boiling but was abolished by incubating venom with trypsin, suggesting peptide involvement. No effect on Xenopus oocyte Ca2+-activated Cl− channels (ClCa) when added to the extracellular or cytosolic side. Purfied ClTx from L. q. quinquestriatus was inactive on CFTR. | [155,156] | |
Georgia anion toxin 1 (GaTX1) | 3.67 | CFTR | Potent, state-dependent (closed channel), reversible blockade of CFTR from the cytosolic side, with KD = 41.5 nM and IC50 = 48 nM. Reduced the open probability and increased the closed time of the channel. Blockade was reduced by high [ATP]. Possibly acts as a non-competitive blocker of CFTR. Greater than 94% identity with cDNA-derived sequences of ClTx-a, -b and -c and >62% sequence identity with various other ClTx-like peptides. No effect when applied to the extracellular surface of CIC-1 and CIC-2 channels or the chloride/H+ exchanger (antiporter) CIC-3, or the cytoplasmic surface of CIC-2 channels. GaTX1 was therefore different from the venom peptide that inhibits CIC-2 channels (see above). At concentrations that affected CFTR, GaTX1 had no effect on GABAC receptors when applied to the extracellular surface, or when applied to the cytosolic side of endogenous Ca2+-activated chloride Cl− channels. Also did not affect the ABC transporters MRP1, MRP2, and MRP3. | [157] | |
Lqh7-1 | 3.65 | Ca2+-regulated Cl− channels | Of three ClTx-related peptides identified (Lqh2-2, Lqh7-1 and Lqh8-6), Lqh7-1 blocked Ca2+-regulated Cl− channels in rat portal vein myocytes (IC50 63 ± 13 nM). Synthetic Lqh-1 caused similar blockade (IC50 49 ± 5 nM). Lqh2-2 caused only 50% blockade at 1 μM, whereas Lqh8-6 was inactive. Lqh7-1 had no effect on L-type and T-type voltage-dependent Ca2+ channels, on intracellular Ca2+ release via ryanodine-sensitive channels, or on Ca2+-activated and voltage-activated K+ currents. | [158] |
3.4. Non-Disulfide-Bridged Peptides (NDBPs)
3.5. Non-Channel-Modulating Peptides
3.6. Enzymes
4. Insecticidal Activity of Scorpion Venoms and Toxins
4.1. Insecticidal Potential
4.2. Practical Considerations Related to Scorpion Toxin-Based Insecticides
5. Therapeutic Applications of Scorpion Venoms and Toxins
5.1. Antibacterial Activity
5.2. Antiviral Activity
5.3. Antifungal Activity
5.4. Antiparasitic Activity
5.5. Autoimmune Diseases
5.6. Antidiabetic Activity
5.7. Anticancer Activity
5.8. Analgesic Activity
5.9. Therapeutic Potential of Scorpion Toxins in Neurological and Neurodegenerative Diseases
6. Challenges and Future Perspectives
- Mechanistic studies: A deeper understanding of the molecular mechanisms of scorpion toxin action in insects is essential for optimizing their insecticidal activity. This includes identifying specific target sites within insect neuronal channels and elucidating the interactions between toxins and these targets. Techniques such as electrophysiology, molecular modeling, and proteomics can be useful in reaching this goal. This should lead to the development of more specific toxins.
- Structure-activity relationship studies: Research on the structure-activity relationships of scorpion toxins is crucial for designing more potent and selective insecticides. By identifying the structural features responsible for insecticidal activity, it should be possible to develop modified toxins with enhanced efficacy and reduced off-target effects. This can be achieved through peptide synthesis and combinatorial chemistry.
- Development of novel delivery systems: Efficient and targeted delivery of scorpion toxin-based insecticides is essential for maximizing their efficacy and minimizing environmental impact. Novel delivery systems, such as nanoencapsulation, liposomes, and viral vectors, can be explored to achieve this goal. These systems can enhance toxin stability, improve target specificity, and reduce the amount of toxin required for pest control [264].
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Species | Origin | Molecule(s) | Nature | Activity | References |
---|---|---|---|---|---|
Aegaeobuthus gibbosus | Turkey | Venom | Venom | Venom was active against Bacillus sphaericus, Bacillus subtilis, Bacillus cereus and Staphylococcus aureus (all Gram-positive) and Escherichia coli (Gram-negative), but not against Enterococcus faecalis and Micrococcus luteus (both Gram-positive) | [316] |
Androctonus aeneas | North Africa | AaeAP1, AaeAP2 | Antimicrobial peptides | Both peptides inhibited S. aureus (MIC: 16 μg/mL), but were much less effective against E. coli (MIC: >512 μg/mL). | [317] |
Androctonus amoreuxi | North Africa | AamAP1, AamAP2 | Antimicrobial peptides | AamP1 and AamAP2 inhibited S. aureus (MIC: 20 and 48 μM, respectively) more effectively than E. coli (MIC: 120 and 150 μM, respectively). | [318] |
GK-19 (AamAP1 derivative) | Antimicrobial peptide | Broad-spectrum antibacterial activity against E. coli, E. faecalis, K. pneumoniae, P. aeruginosa and S. aureus (MIC: 3–10 μM). Disrupted bacterial membranes. | [319] | ||
Androctonus australis | Algeria | Venom and peptide G-TI | Sodium channel inhibitor | Venom was active against B. cereus, E. coli, Microcossus spp. and S. aureus (MIC: 75, 150, 125, and 125 μg/mL, respectively). Disrupted bacterial membranes, leading to cell death. The peptide G-TI was active against B. cereus. | [320] |
Androctonus crassicauda | Saudi Arabia | Venom | Venom | Inhibited the growth of E. coli, Salmonella spp., S. aureus, and Paenibacillus larvae. | [321] |
Turkey | Venom | Venom | Venom was active against Bacillus cereus, Bacillus sphaericus, Bacillus subtilis, Escherichia coli, and Micrococcus luteus, but not against Enterococcus faecalis and Staphylococcus aureus. | [316] | |
Hottentotta saulcyi | Turkey | Venom | Venom | Venom was active against Bacillus cereus, Bacillus sphaericus, Bacillus subtilis, Enterococcus faecalis and Staphylococcus aureus, but not against Escherichia coli or Micrococcus luteus. | [316] |
Leiurus abdullahbayrami | Turkey | Venom | Venom | Venom was active against Bacillus sphaericus, but not against Bacillus cereus, Bacillus subtilis, Enterococcus faecalis, Escherichia coli, Micrococcus luteus or Staphylococcus aureus. | [316] |
Leiurus quinquestriatus | Egypt | Venom | Venom | Inhibited B. subtilis and C. freundii; no effect on B. cereus and K. pneumoniae. | [322] |
Saudi Arabia | Venom | Venom | Inhibited the growth of E. coli, Salmonella spp., S. aureus, and Paenibacillus larvae. More effective than A. crassicauda venom | [321] | |
Saudi Arabia | Venom | Venom | Concentration-dependent inhibition of A. baumannii, E. coli, E. faecalis, K. pneumoniae, P. aeruginosa, and S. aureus. | [323] | |
Odontobuthus doriae | Iran | Peptide 3 | Venom fraction | Inhibited Enterococcus faecalis and Escherichia coli UT189 (IC50: 160 and 80 μg/mL, respectively). | [324] |
Pandinus imperator | North Africa | Scorpine | Antimicrobial peptide | Inhibited B. subtilis and K. pneumoniae (MIC: 1 and 10 μM, respectively). | [325] |
Protoiurus kraepelini | Turkey | Venom | Venom | High bactericidal activity, with inhibition zones of 9–20 mm against Bacillus sphaericus, Bacillus cereus, Bacillus subtilis, Enterococcus faecalis, Escherichia coli, Micrococcus luteus and Staphylococcus aureus. | [316] |
Scorpio maurus palmatus | Egypt | Smp24, Smp43 | Antimicrobial peptides | Disrupted bacterial membranes, with activity against Bacillus subtilis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus and Staphylococcus epidermidis. Smp43 also interfered with B. subtilis DNA synthesis. Caused pore formation and induced oxidative stress in E. coli (MIC: 4–128 μg/mL). Greater efficacy against Gram-positive bacteria. | [326,327] |
Species | Origin | Molecule(s) | Nature | Activity | References |
---|---|---|---|---|---|
Buthus occitanus tunetanus | Tunisia | BotCl | Chlorotoxin-like peptide | Concentration-dependent inhibition of Newcastle disease virus in avian species, with an IC50 of 0.69 μM. Mechanism involves direct disruption of viral particle structure, preventing cellular entry and proliferation. | [331] |
Mesobuthus eupeus | Iran | Mucin 13, Mucin 18 | Antimicrobial peptides | Potential antiviral activity against SARS-CoV-2 by targeting the receptor-binding domain (RBD) of the spike protein. Mucin-18 shows stronger binding affinity, with the A9T mutation enhancing its effectiveness. | [332] |
Odontobuthus doriae | Iran | ODAMP2, ODAMP5 | Antimicrobial peptides | Computational studies suggest high binding affinities to the SARS-CoV-2 spike protein’s receptor binding domain, with binding energies of −59.2 and −51.8 kcal/mol for ODAMP2 and ODAMP5, respectively, indicating potential efficacy. | [333] |
Scorpio maurus palmatus | Egypt | Venom | Venom | Significant activity against hepatitis C virus (HCV), interfering with viral entry. IC50 of 6.3 μg/mL, selectivity index of 15.8. Activity is independent of enzymatic processes and specific to Flaviviridae viruses such as HCV and Dengue virus (DENV). | [334] |
Egypt | Smp76 | Scorpine-like peptide | Potent antiviral activity against HCV and DENV, inhibiting early infection stages, likely Via direct viral particle interaction. IC50 of 0.01 μg/mL for both viruses. No cytotoxic or hemolytic effects at concentrations exceeding 1000 times the antiviral dose. | [335] |
Species | Origin | Molecule(s) | Nature | Activity | References |
---|---|---|---|---|---|
Androctonus aeneas | North Africa | AaeAP1, AaeAP2 | Antimicrobial peptides | Inhibits Candida albicans (MIC: 32 μg/mL). | [317] |
Androctonus amoreuxi | North Africa | GK-19 | Derived from AamAP1 | Shows strong antifungal activity against Candida albicans, Candida glabrata and Candida krusei (MIC: 5–10 µM). Disrupts fungal membranes, causing structural damage. | [319] |
Androctonus australis | North Africa | AamAP1, AamP2 | Antimicrobial peptides | Inhibits Candida albicans (MIC: 64 µM). | [42] |
North Africa | Androctonin | Cysteine-rich antimicrobial peptide | Exhibits potent antifungal activity against various fungal species, particularly Verticillium torelis and Fusarium oxysporum (MIC: <4 µM). Completely inhibits Neurospora crassa spore growth at ≥12 µM, without regrowth. | [340] | |
Leiurus quinquestriatus | Saudi Arabia | Venom | Venom | Reduces growth and survival of Candida albicans (by 31.2%) and Candida glabrata (by 39.0%). | [323] |
Species | Origin | Molecule(s) | Nature | Activity | References |
---|---|---|---|---|---|
Androctonus crassicauda | Egypt | Venom | Venom | Antihelminthic activity against Trichuris arvicolae that involved significant ultrastructural changes. Potential use in the treatment of gastrointestinal nematodes resistant to conventional drugs. | [342] |
Saudi Arabia | Venom | Venom | Complete destruction of Echinococcus granulosus protoscolices after 4 h of exposure at 100 μg/mL. The damage involved apoptosis and structural alterations. Potential use in the non-surgical treatment for hydatidosis, a significant public health problem. | [343] | |
Hemiscorpius lepturus | Iran | Fraction 5 | Venom peptide fraction (<10 kDa) | Reduced the viability of Toxoplasma gondii tachyzoites at 100 μg after 2 h. | [341] |
Mesobuthus eupeus | Iran | Mucin 24, Mucin 25 | Antimicrobial peptides | Inhibited Plasmodium falciparum without harming human cells (erythrocytes and GC-2 cells), and prevented P. berghei ookinete growth at 10–20 μM, possibly via membrane disruption. | [344] |
Mesobuthus eupeus | Iran | Fraction 8 | Venom peptide fraction (<10 kDa) | Scolicidal activity against Echinococcus granulosus protoscolices within 30 min of exposure to venom fraction. | [345] |
Pandinus imperator | North Africa | Scorpine | Antimicrobial peptide | Activity against Plasmodium berghei, involving disruption of sexual stage development in mosquito midguts. Inhibition of fertilization and ookinete formation with ED50 of 10 μM and 0.7 μM, respectively, an effect attributed to membrane disruption. | [325] |
Species | Origin | Molecule(s) | Activity | References |
---|---|---|---|---|
Androctonus australis hector | Algeria | Venom Fraction F1 | Treatment with Fraction F1 (10 mg/kg, i.p.; daily for 11 days) restored the body weight gain, attenuated the diabetes-induced hyperglycemia and improved the glucose tolerance in mice with streptozotocin-induced diabetes. Fraction F1 improved β-cell function and survival and increased the mitotic activity of these cells. Characterization of Fraction F1 revealed the presence of hyaluronidase and peptides, potentially contributing to glucose homeostasis and β-cell survival. | [350] |
Leiurus quinquestriatus | Egypt | Venom | Venom (daily injection of 1/10 of the lethal dose for eight weeks) normalized the blood glucose levels and body weight in rats with streptozotocin-induced diabetes. The venom prevented the histopathological and immunohistochemical changes caused by diabetes in splenic tissues. | [351] |
Egypt | Venom | Venom (daily injection of 1/40 of the sublethal dose for eight weeks) prevented body weight loss, normalized hematological parameters, blood cell counts and blood glucose levels, reduced C-peptide levels to slightly below normal, normalized indicators of hepatic function and indicators of oxidative stress, and promoted β islets regeneration in rats with streptozotocin-induced diabetes. | [352] |
Species | Origin | Molecule(s) | Nature | Activity | References |
---|---|---|---|---|---|
Androctonus australis | Tunisia | P01 | K+ channel toxin | Inhibits proliferation, adhesion, and migration of U87 glioblastoma cells. | [357] |
Tunisia | AaTs-1 | Tetrapeptide | Inhibits glioblastoma U87 cell proliferation, modulates kinase expression, and enhances p53 and FPRL-1 expression. | [358] | |
Tunisia | AaTs-1-4B | Dendrimer multi-branched molecules | Inhibits U87 cell proliferation and migration, enhances ERK1/2 and AKT phosphorylation, and increases p53 expression. | [359] | |
Androctonus australis hector | Algeria | F3 fraction | Venom fraction | Induces apoptosis in lung cancer cells (NCI-H358) via the mitochondrial pathway. | [360] |
Algeria | Venom | Venom | Alters alveolar epithelial cell (A549) integrity, disrupts cytoskeleton, and reduces cell migration. | [361] | |
Androctonus crassicauda | Turkey | Acra3 | Na+ channel toxin | Cytotoxic to BC3H1 cells and induces necrosis. | [362] |
Androctonus crassicauda, Androctonus bicolor, Leiurus quinquestriatus | Saudi Arabia | Venom | Venom | Inhibits cell proliferation, motility, and colony formation in colorectal and breast cancer cells. | [363,364] |
Buthus occitanus | Morocco | α-Insect toxin Lqq3, α-Like toxin Bom4 | Na+ channel toxin | Inhibits hepatocellular carcinoma cell proliferation (Huh 7.5 cells in 3D culture). | [365] |
Buthus occitanus tunetanus | Tunisia | RK1 | Short peptide (14 amino acids) | Inhibits cell proliferation, migration, and angiogenesis in U87 and IGR39 cells. | [366] |
Euscorpius mingrelicus | Turkey | Venom | Venom | Cytotoxicity towards breast and lung cancer cells by inducing apoptosis and necrosis. | [367] |
Hemiscorpius lepturus | Iran | Leptulipin | Phospholipase A2 | Inhibits proliferation, alters morphology, induces DNA fragmentation, and cell cycle arrest in HT-29 and MDA-MB-231 cells. | [368] |
Hottentotta saulcyi | Iran | Venom | Venom | Induces apoptosis in MCF-7 cells, reduces tumor density in vivo, and upregulates pro-apoptotic genes. | [369] |
Hottentotta Schach | Iran | Venom | Venom | Antiproliferative activity in MCF-7 cells by inducing oxidative stress leading to apoptosis. | [370] |
Leiurus quinquestriatus | Egypt | GNPs-V | Venom conjugated with gold nanoparticles | Anticancer activity against liver cancer cell lines by inhibiting migration, inducing cell cycle arrest, and promoting apoptosis. | [371] |
Israel | Chlorotoxin | Cl− channel toxin | Targets glioblastoma multiform cells, inhibits angiogenesis, and binds to specific channels. | [372] | |
Saudi Arabia | FLV-SV | Fluvastatin-scorpion venom peptide nano-conjugate | Antiproliferative activity in colorectal adenocarcinoma cells. | [373] | |
Saudi Arabia | THQ–PL–SV | Thymoquinone-phospholipon-scorpion venom peptide nanovesicles | Antiproliferative activity in lung cancer cells through modulation of gene expression. | [374] | |
Mesobuthus eupeus | Iran | meuCl14 | Chlorotoxin | Inhibits hMMP-2 and limits tumor progression. | [167] |
Iran | MeICT | Cl− channel toxin | Inhibits glioma cell proliferation and migration; downregulates Annexin A2 and FOXM1. | [375] | |
Odontobuthus bidentatus | Iran | Venom | Venom | Induces apoptosis in HepG2 cells via increased nitric oxide levels. Antiproliferative activity in MCF-7 cells. | [376,377] |
Odontobuthus doriae | Iran | Venom | Venom | Apoptotic and antiproliferative activity in human neuroblastoma (SH-SY5Y) and human breast cancer (MCF-7) cells | [378,379] |
Protoiurus kraepelini | Turkey | Venom | Venom | Concentration-dependent cytotoxicity in Jurkat cells. | [380] |
Scorpio maurus palmatus | Egypt | Smp24 | Cationic antimicrobial peptide | Suppresses lung cancer cell growth, and induces apoptosis, cell cycle arrest, and autophagy in HepG2 cells. | [381,382] |
Egypt | Smp43 | Cationic antimicrobial peptide | Inhibits lung cancer cell proliferation, causes membrane rupture and mitochondrial dysfunction, and alters apoptosis, cell cycle, and autophagy. Inhibits hepatocellular carcinoma cells. | [383,384] |
Species | Origin | Molecule(s) | Toxin Class | Activity | References |
---|---|---|---|---|---|
Androctonus amoreuxi | Egypt | Venom | - | Dose-dependent reduction in acetic acid-induced writhing (peripheral pain) and increased latency in the tail flick test (central pain). | [404] |
Androctonus mauretanicusmauretanicus | Morocco | anatoxin Amm VIII | NaTx | Dose-dependent analgesia in hot plate and tail flick tests. Antinociception mediated by blockade of Nav1.2, activation of endogenous opioid system, and activation of mechanisms involving diffuse noxious inhibitory controls (DNIC). | [399,405] |
Buthus occitanus tunetanus | Tunisia | BotAF | NaTx | Non-toxic β-toxin-like peptide with no effect on motor activity. Reversible low blockade (≤20%) of Na+ channels. Peripheral or spinal mechanisms involved in attenuating the pain associated with the acetic acid writhing, formalin, hot plate, and tail-flick assays. Analgesic activity independent of opioid system. More potent than β-endorphin or morphine in these tests. Effective when given i.p., but not when given i.v. or i.c.v. Low activity on TTX-S Na+ channels of DRG and does not bind to rat brain synaptosomes. Stimulates lumbar spinal cord c-fos/c-jun mRNA up regulation. | [406] |
Hemiscorpius lepturus | Iran | Leptucin | ND | Analgesic effect against acute thermal pain (hot plate and tail-flick tests) at doses of 0.32 and 0.64 mg/kg, i.p., with similar or greater activity than morphine. No cytotoxicity or hemolysis. No histopathological alterations in heart, kidney or liver. LD50 (mice) > 4 mg/kg. | [407] |
Heterometrus laoticus | Vietnam | Venom | KTx | Venom showed analgesic activity (9.5 and 19 mg/kg) in the tail immersion (55 °C water) and tail flick assays that was less potent than morphine (5 mg/kg). A short K+ channel toxin (Hetlaxin) that blocks Kv1.1 and Kv1.3, with high affinity for the latter (Ki = 59 nM), was isolated from the venom, but its analgesic activity in the assays indicated above was not tested. | [398] |
Leiurus q. quinquestriatus | Sudan | LqqIT2 | NaTx | Dose-dependent analgesia in hot plate and tail flick tests. Antinociception mediated by blockade of Nav1.2, activation of endogenous opioid system, and activation of mechanisms involving diffuse noxious inhibitory controls (DNIC). | [398] |
Mesobuthus martensii | China | ANEP (Anti-neuroexcitation peptide) | NaTx | β-Toxin that blocks Nav1.7. Analgesic activity in the mouse acetic acid writhing test and hot plate test. Recombinant peptide has same activity as native peptide. Several mutants showed greater activity than the recombinant peptide. | [408,409] |
China | BmK-YA 8 | Short-chain NDBP | Structurally related to enkephalin. Activates μ, κ and δ opioid receptors, with selectivity for δ opioid receptors ~7- and 12-fold greater than for µ and κ receptors, respectively. Full agonist at δ opioid receptors, and partial agonist with lower efficacy and potency on μ and κ receptors. Activity at δ opioid receptors antagonized by naloxone. | [400] | |
BmK AGAP (Analgesic-antitumor peptide) | NaTx | Blockade of Nav1.4, Nav1.5, Nav1.7, Nav1.8, TRPV1, and KCNQ2/3 currents. Analgesic activity in the writhing, hot-plate and formalin tests. Attenuation of pain in the formalin-induced spontaneous nociceptive behavior assay involved inhibition of the expression of peripheral and spinal mitogen-activated protein kinases (MAPK), including p-p38, p-ERK, p-JNK and spinal Fos. Intrathecal administration of AGAP inhibited and reversed pain from chronic constrictive injury (CCI) of the sciatic nerve, from thermal hyperalgesia, and mechanical allodynia. Potentiated the analgesic effect of lidocaine. | [410,411,412,413] | ||
China | BmK AS | NaTx | Blockade of TTX-R (Nav1.8, 1.9) and TTX-S (Nav1.3), with no effect on voltage-dependent IK and KCl or caffeine-induced Ca2+ influx in neurons. Decreased the number of action potentials in DRG neurons by ~50% at 0.5 μM. Analgesic activity in formalin and carrageenan nociceptive assays. | [414] | |
China | BmK AngM1 | NaTx | Little or no toxicity at doses up to 50 mg/kg, i.v. Irreversible (by washing) blockade of Nav and delayed rectifier K+ (IK) currents, but no effect on transient K+ currents (IA) in rat hippocampal pyramidal neurons. Analgesic effect in acetic acid writhing assay in mice (63% inhibition at 0.8 mg/kg, compared to 83% with morphine 0.2 mg/kg, i.v.). | [415] | |
China | DKK-SP2 | NaTx | Blocked Nav1.7 channels expressed in Chinese hamster ovary cells and reduced the expression of this channel in trigeminal neurons. Reduced writhing in the acetic acid test in mice and pain associated with chronic constriction injury of the infraorbital nerve in rats was also attenuated. At the highest doses tested, the potency in both tests was similar to or better than morphine. | [416] | |
China | BmKBTx, BmNaL-3SS2 | NaTx | Blockade of Nav1.7. BmKBTx and BmNal-3SS2 reducing writhing in the acetic acid test in mice and show similar potency to morphine (reductions of 43% and 63% at 1 mg/kg i.p., respectively, compared to 49% with morphine 1.5 mg/kg i.p.). | [417] | |
China | Syb-prII | NaTx | β-Neurotoxin that blocks Nav1.8, but not Nav1.9. Attenuated pain associated with chronic constriction injury of the infraorbital nerve, probably by attenuating MAPK-activated pathways. Efficacy similar to morphine. | [418] | |
Tityus serrulatus | Brazil | TsNTxP | NaTx | Non-toxic peptide structurally related to toxins TsVII (Ts1 or toxin-γ) and Ts3 (TsIV or tityustoxin). Non-toxic to mammals. Antinociceptive effect in tail-flick thermal test and intraplantar capsaisin injection. Attenuates neuropathic pain caused by constriction injury to sciatic nerve and paclitaxel administration. Caused reduced glutamate release from mouse spinal cord synaptosomes. | [419] |
Species | Toxin | Toxin Characteristics | Therapeutic Potential |
---|---|---|---|
Androctonus australis | AaTx | One of a family of peptides that primarily targets Na+ channels | Shows immunomodulatory activity, including specific targeting of Kv1.3 channels involved in T cell-mediated autoimmune responses [424]. As oxidative stress is a major contributor to dopaminergic neuron loss in Parkinson´s disease and amyloid pathology in Alzheimer´s disease, AaTx could represent a potentially useful lead compound for developing therapeutic drugs for these neurodegenerative diseases. |
B. martensii Karsch | BmK AngP1 | A 62-amino acid peptide with high sequence homology to neurotoxins that target ion channels, but it exerts non-toxic and neurotrophic effects | Promotes angiogenesis and neurogenesis in hippocampal neurons through modulation of pathways related to VEGF expression and PI3K/Akt signaling, both relevant to neuronal survival. In rodent models, this peptide reduces oxidative stress, neuroinflammation, and amyloid-β accumulation, suggesting a protective role against neurodegeneration [425,426]. |
B. martensii Karsch | BmK CT | A small peptide (~36–40 amino acids) structurally related to chlorotoxin (chlorotoxin-like peptide) and capable of crossing the Blood–Brain Barrier (BBB). | Inhibits matrix metalloproteinase 2 (MMP-2), an enzyme overexpressed in neuroinflammation and tumors. Exhibits anti-inflammatory properties in models of neuroinflammation by suppressing IL-6 and TNF-α [427]. As chronic neuroinflammation is driven by cytokines and MMPs contributes to neurodegeneration, BmK CT could mitigate these pathways. |
B. martensii Karsch | BmK NSPK (Neuroprotective scorpion peptide Karsch | A low-molecular-weight peptide the structure of which has yet to be solved. | Shows CNS bioactivity without the neurotoxicity of classic neurotoxins. As part of its protective mechanism of action, BmK NSPK improves mitochondrial membrane potential and ATP production in primary cortical neurons, and inhibits Aβ-induced neuronal apoptosis by regulating Bcl-2/Bax ratios and caspase-3 activity [428]. |
B. martensii Karsch | BmK AGAP (Analgesic-antitumor peptide) | A 66-amino acid peptide originally isolated for its analgesic and anti-tumor effects. | Suppresses microglial activation and reduces secretion of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6). Inhibits p38 MAPK and ERK1/2 signaling pathways, key regulators of inflammatory and apoptotic signaling in activated microglia [413]. |
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Dal Belo, C.A.; Hyslop, S.; Carlini, C.R. Properties and Pharmacology of Scorpion Toxins and Their Biotechnological Potential in Agriculture and Medicine. Toxins 2025, 17, 497. https://doi.org/10.3390/toxins17100497
Dal Belo CA, Hyslop S, Carlini CR. Properties and Pharmacology of Scorpion Toxins and Their Biotechnological Potential in Agriculture and Medicine. Toxins. 2025; 17(10):497. https://doi.org/10.3390/toxins17100497
Chicago/Turabian StyleDal Belo, Cháriston André, Stephen Hyslop, and Célia Regina Carlini. 2025. "Properties and Pharmacology of Scorpion Toxins and Their Biotechnological Potential in Agriculture and Medicine" Toxins 17, no. 10: 497. https://doi.org/10.3390/toxins17100497
APA StyleDal Belo, C. A., Hyslop, S., & Carlini, C. R. (2025). Properties and Pharmacology of Scorpion Toxins and Their Biotechnological Potential in Agriculture and Medicine. Toxins, 17(10), 497. https://doi.org/10.3390/toxins17100497