Scorpions are well known for their dangerous stings that can result in severe consequences for human beings, including death. Neurotoxins present in their venoms are responsible for their toxicity. Due to their medical relevance, toxins have been the driving force in the scorpion natural compounds research field. On the other hand, for thousands of years, scorpions and their venoms have been applied in traditional medicine, mainly in Asia and Africa. With the remarkable growth in the number of characterized scorpion venom components, several drug candidates have been found with the potential to tackle many of the emerging global medical threats. Scorpions have become a valuable source of biologically active molecules, from novel antibiotics to potential anticancer therapeutics. Other venom components have drawn attention as useful scaffolds for the development of drugs. This review summarizes the most promising candidates for drug development that have been isolated from scorpion venoms.

SUMMARY The number and types of venom components that affect ion-channel function are reviewed. These are the most important venom components responsible for human intoxication, deserving medical attention, often requiring the use of specific anti-venoms. Special emphasis is given to peptides that recognize Na+-, K+- and Ca++-channels of excitable cells. Knowledge generated by direct isolation of peptides from venom and components deduced from cloned genes, whose amino acid sequences are deposited into databanks are now adays in the order of 1.5 thousands, out of an estimate biodiversity closed to 300,000. Here the diversity of components is briefly reviewed with mention to specific references. Structural characteristic are discussed with examples taken from published work. The principal mechanisms of action of the three different types of peptides are also reviewed. Na+-channel specific venom components usually are modifier of the open and closing kinetic mechanisms of the ion-channels, whereas peptides affecting K+-channels are normally pore blocking agents. The Ryanodine Ca++-channel specific peptides are known for causing sub-conducting stages of the channels conductance and some were shown to be able to internalize penetrating inside the muscle cells.

Excitation-contraction coupling in skeletal muscle is believed to be triggered by direct protein-protein interactions between the sarcolemmal dihydropyridine-sensitive Ca 2؉ channel and the Ca 2؉ release channel/ryanodine receptor (RyR) of sarcoplasmic reticulum. A 138-amino acid cytoplasmic loop between repeats II and III of the ␣ 1 subunit of the skeletal dihydropyridine receptor (the II-III loop) interacts with a region of the RyR to elicit Ca 2؉ release. In addition, small segments (10 -20 amino acid residues) of the II-III loop retain the capacity to activate Ca 2؉ release. Imperatoxin A, a 33-amino acid peptide from the scorpion Pandinus imperator, binds directly to the RyR and displays structural and functional homology with an activating segment of the II-III loop (Glu 666 -Leu 690 ). Mutations in a structural motif composed of a cluster of basic amino acids followed by Ser or Thr dramatically reduce or completely abolish the capacity of the peptides to activate RyRs. Thus, the Imperatoxin A-RyR interaction mimics critical molecular characteristics of the II-III loop-RyR interaction and may be a useful tool to elucidate the molecular mechanism that couples membrane depolarization to sarcoplasmic reticulum Ca 2؉ release in vivo.

A new antimicrobial peptide, hadrurin, was isolated from the venom of the Mexican scorpion Hadrurus aztecus, by gel filtration on a Sephadex G-50 column, followed by high performance liquid chromatography. It is a basic peptide composed of 41 amino-acid residues with a molecular mass of 4436 Da, and contains no cysteines. A model of the three-dimensional folding of hadrurin is compatible with that of an amphipatic molecule with two a-helical segments. Hadrurin demonstrates antimicrobial activity at low micromolar concentration, inhibiting the growth of bacteria such as: Salmonella thyphi, Klebsiella pneumoniae, Enterococcus cloacae, Pseudomonas aeruginosa, Escherichia coli and Serratia marscences. It also shows cytolytic activity when tested in human erythrocytes. Hadrurin and two analogs (C-terminal amidated, and all d-enantiomer) were chemically synthesized. They were used to study the possible molecular mechanism of action by testing their ability to dissipate the diffusion potential of liposomes of different compositions. The results obtained indicate that there are no specific receptor molecules for the action of hadrurin, and the most probable mechanism is through a membrane destabilization activity. It is surmised that hadrurin is used by the scorpion as both an attack and defense element against its prey and putative invasive microorganisms. It is a unique peptide among all known antimicrobial peptides described, only partially similar to the N-terminal segment of gaegurin 4 and brevinin 2e, isolated from frog skin. It would certainly be a model molecule for studying new antibiotic activities and peptide±lipid interactions. . Most of these peptides share some common characteristics such as their low molecular mass (2±5 kDa), the presence of multiple lysine and arginine residues, and their amphipatic nature. Their site of action is the cytoplasmic membrane, where they destabilize its lipid package and produce transient channels (reviewed in [26±28]). However, it seems that the primary action of some of them, such as PR39 [29,30], is not directed towards the membrane, and it is believed that for plant defensins there exists a receptor [31,32];. Although the minimal inhibitory concentrations (1±50 mm) of these molecules are high in comparison to other antibiotics, their broad activity spectra and speed of action makes them good candidates for delivering drugs, and a number of possible applications have already been described (reviewed in [33]).Scorpion venom has been traditionally studied for the presence of neurotoxins that affect ion channels: sodium, potassium, calcium and chloride [34], and very little is known about peptides with different activity. Antimicrobial peptides have been isolated from the venom of spider [35], hornet [23] and bee [16].This communication reports the isolation of a novel antibacterial and cytolytic peptide constitutively present in the venom of the scorpion Hadrurus aztecus. It has a unique sequence, quite different from other antimicrobial peptides isolated from the hemolymp...

Resurgent currents are functionally crucial in sustaining the high frequency firing of cerebellar Purkinje neurons expressing Na v 1.6 channels. ␤-Scorpion toxins, such as CssIV, induce a left shift in the voltage-dependent activation of Na v 1.2 channels by "trapping" the IIS4 voltage sensor segment. We found that the dangerous Cn2 ␤-scorpion peptide induces both the left shift voltage-dependent activation and a transient resurgent current only in human Na v 1.6 channels (among 1.1-1.7), whereas CssIV did not induce the resurgent current. Cn2 also produced both actions in mouse Purkinje cells. These findings suggest that only distinct ␤-toxins produce resurgent currents. We suggest that the novel and unique selectivity of Cn2 could make it a model drug to replace deep brain stimulation of the subthalamic nucleus in patients with Parkinson disease.