Therapeutic Potential of Scorpion Venoms Components: Bioactive Peptides and their Pharmacological Submissions

Scorpion venoms contain numerous biologically active substances, such as neurotoxins active on ion channels, enzymes, nucleotides, lipids, mucoproteins, biogenic amines, glycosaminoglycans, histamine, as well as other molecules that have not yet been identified [1-5]. Plentiful molecules endowed with biological activities have been purified from scorpion venoms, including antibacterial, antifungal, antiviral, antimalarial, antitumor, and immunomodulatory activities. Furthermore, a strong structure/function relationship has been explored in many research and point the role of cysteine residues and disulfide bond linkages in the creation of different structures and molecular architectures [6]. The present short review on peptides or scorpion venom components shows a summary of these natural bioactive molecules.

Antibacterial peptides

More than 40 peptides have been purified from the venoms of various scorpion species. These peptides endowed with antimicrobial activity are either NDBP or DBP peptides with a short or long peptide chain. Antibacterial activity was found in the venoms of Hadrurus aztecus, Isometrus maculatus, and Tityus discrepans, demonstrating an effect on Salmonella typhi, Klebsiella pneumoniae, Enterococcus cloacae, and Bacillus subtilis [7-9]. In addition to their toxic and anti-insect effects, other activities have been highlighted. This is the case for BmK IT-AP, an anti-insect toxin isolated from the venom of Buthus martensi Karsch, which exhibits an analgesic effect in mice. Another Analgesic Peptide, BmK (AGAP), was also purified from the venom of Buthus martensi Karsch; it exhibits an analgesic effect on visceral pain and antitumor activity against E. ascites cells and S-180 fibrosarcomas [2,10].

Antifungal peptides

Fungi such as Candida, Cryptococcus, and Aspergillus fumigatus form a group of pathogens that affect health. Infections caused by these germs range from mucosal infections to invasive aspergillosis infections [11]. Just like bacteria, these fungi develop resistance to antifungals. Several peptides purified from scorpion venoms exhibit antifungal activity, such as Opistoporin 1 (purified from the venom of Opistophthalmus carinatus) and parabutoporin (purified from the venom of Parabuthus schlechteri), which inhibit 50% of the growth of Saccharomyces cerevisiae at 2nM [12]. Pandinine 2, purified from the venom of Pandinus imperator, exhibits activity against Candida albicans with a MIC of 19.1mM [13]. Meucine 18, purified from the venom of Mesobuthus eupeus, has activity against Aspergillus fumigatus, Candida albicans, and Saccharomyces cerevisiae with lethal doses of 8.3, 25.1, and 10.9mM, respectively [13,14].

Antimalarial peptides

Morbidity and mortality due to malaria caused by the parasite Plasmodium falciparum remain a public health problem, especially in the Saharan regions of Africa and Southeast Asia [15]. A peptide named scorpine-the first peptide isolated from the venom of the scorpion Pandinus imperator-exhibits antibacterial activity and a potent inhibitory effect on the oocyte stages and gametes of Plasmodium berghei at a dose of 70mM [10,16]. Two other NDBP peptides with antimalarial activity have been identified, cloned from cDNA obtained from the venom of Mesobuthus eupeus: meucine 24 and meucine 25. These two molecules are capable of inhibiting the development of Plasmodium berghei oocytes at concentrations of 10 and 20mM. A significant reduction in the parasite density of Plasmodium falciparum within erythrocytes was observed 48hours post-treatment with a 10mM dose of these peptides [17].

Antiviral peptides

The emergence of viral infections represents a major complication in human health. Few scorpion peptides possess antiviral activity. The first peptide purified from the venom of Heterometrus petersii, Hp1090, inhibited the growth of hepatitis C in vitro with an IC50 of 5 and 13mM; this peptide inhibits the amplification of HCV RNA in Huh7.5.1 cells [18]. Another peptide, initially showing antimicrobial activity, was also found to possess antiviral potency against SARS coronavirus (EC50 of 7.12mM) and against influenza A (H5N1) with an EC50 of 1.03 mM [4].

Analgesic peptides

Neurotoxins from scorpion venoms are targeting mainly Voltage Gated Channels (VGC) like VGSC for sodium, VGPC for potassium and VGCC for calcium which explain pain felt after scorpion envenoming. The blockers targeting VGSCs and activators targeting VGPCs could be a useful to treat pain. Comprehensive studies on biochemical properties and structural forms revealed different channels subtypes which have opened a convenient alternative to block specifically these channels with highly specific peptides. These subtypes are represented by some of them like Kv 1.1, Kv 1.2., Kv 2.1, Kv 2.2, Cav 2.1, Cav 2.2, Nav 1.1, Nav 1.3, Nav 1.6, Nav 1.7, Nav 1.8, Nav 1.9, the last three ones are more involved in pain, these subtypes Peptides characterised from scorpion venom showed an analgesic effect. Molecular studies and research provide an explanation and presented a list of these peptides. BmK AGAP the most effective one could blockade the Nav 1.4, Nav 1.5, Nav 1.7, Nav 1.8., Makatoxin 3 could blockade the Nav 1.7.

Anticancer peptides

Antitumor activity has been reported in the composition of several scorpion venoms. This is the case for peptides isolated from the venoms of Androctonus crassicauda (Acra3) and Tityus discrepans (neopladinel 1 and 2), which present antitumor activity on a cell line (BC3H1) and on the SKBR3 cell line (breast cancer cell), respectively [19,20]. An antiproliferative activity of Indian black scorpion venom on U937 and K562 leukemic cells has also been reported, involving the mitochondrial pathway and the inhibition of HSP proteins. Chlorotoxin (ChTx) is the first chlorotoxin purified from the venom of Leiurus quinquestriatus. This toxin binds to chloride channels expressed specifically on human glioma and astrocytoma cells, but does not bind to normal human cells, including neurons [21-24]. ChTx inhibits chloride channels through its binding to the metalloproteinase MMP-2. This chlorotoxin induces the endocytosis of MMP-2 along with the channel (ClC-3, a subtype of chloride channel upregulated on glioma membranes), causing the depletion of these chloride channels in the glioma [25,26]. On the other hand, the study by Liu and collaborators [27] shows the inhibitory effect of ChTx on the migration of STTG1 and U251-MG cells, but the inhibition of chloride channels is not solely responsible for this inhibition. Another recent study shows that a “liposome complex carrying ChTx” significantly inhibits the growth of 4T1 cells derived from a breast tumor in BALB/c mice [28] (Table 1).

Table 1:Summary table of toxins and molecules purified from scorpion venoms endowed with biological activities.

Scorpion venoms represent a vast and largely untapped bioresource of highly specific molecules with immense pharmacological potential [29-36]. Far beyond their traditional classification as hazardous toxins, purified scorpion peptides, ranging from short and long non-disulfide-bridged peptides to specialized ion channel blockers demonstrate potent, multi-targeted biological activities. Their demonstrated efficacy against resistant bacterial pathogens, invasive fungal strains, viral proliferation, and parasitic life stages highlights their promise in combating emerging infectious diseases [37-42]. Furthermore, the high selectivity of specific toxins like Chlorotoxin for malignant tumour cells coupled with their ability to spare healthy tissues, covers the way for highly targeted oncological therapies and precision drug delivery systems. As advances in venomics, peptide synthesis, and biotechnology continue to overcome challenges related to yield and toxicity, scorpion venom components are uniquely positioned to serve as critical lead compounds for next-generation biopharmaceuticals and targeted therapeutics.

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