Personal Use Only Not for Distribution

Send Orders for Reprints to [email protected]

Protein & Peptide Letters, 2018, 25, 702-708

REVIEW ARTICLE ISSN: 0929-8665 eISSN: 1875-5305

Impact Factor: 1.039

Scorpion Venom Peptides as a Potential Source for Human Drug Candidates BENTHAM SCIENCE

1 Bushra Uzair1, Sarah Bint-e-Irshad , Barkat5 Ali Khan2, Beenish Azad1, Tariq Mahmood3,*, 4 Mujaddad Ur Rehman and Valdir A Braga

1

Department of Bioinformatics and Biotechnology, International Islamic University, Islamabad, Pakistan; 2Faculty of Pharmacy, Gomal University, D.I Khan, KPK, Pakistan; 3Faculty of Pharmacy, University of Central Punjab, Lahore, Pakistan; 4Department of Microbiology Abbotabad University, Abbotabad, Pakistan; 5Biotechnology Center, Federal University of Paraiba, Brazil

ARTICLE HISTORY Received: September 21, 2017 Revised: October 23, 2017 Accepted: February 20, 2018

Pe N rs ot on fo al rD U is se tri O bu n tio ly n

Protein & Peptide Letters

702

DOI: 10.2174/0929866525666180614114307

Abstract: Background: Scorpion venom is the most expensive and deadly venom with exciting medical prospects and having a potential as a source of drug candidates. A number of scorpion venom peptides have shown promising site specificity and are involved in the regulation of biological mechanisms. Due to the structural and functional specificity, the scorpion peptides are widely used for the development of specific drugs especially for the cardiovascular and other immune diseases. In this review, we summarize scorpion venom’s biological activities such as antimicrobial, antiviral, anti-cancerous and in immune diseases. Evolutionary perspective of peptides derived from different scorpion venoms are also described in this review. The most significant venom peptides are; Ctriporin, Chlorotoxins (cltx), Neopladine I and II, Meucin 24, Meucin 25 and Hp 1090. The most recognized scorpion species with pharmaceutical activities are; Pandinus imperator, Chaerilustricostatus, Buthus martensii, Mesobuthus eupeus, Leiurus quinnquestriatus, Tityus discrepans and Heterometrus bengalensis. Conclusion: The role of peptides in cardiovascular events and in treating osteoporosis signifies their importance. The role of peptides against pathogens, skin infections, pain-relieving effects, anti-malarial and anti-viral effects are discussed in detail. We further, summarized the classification of scorpion peptides among different toxins, their evolutionary process and the pattern of scorpion venom resource analysis.

Keywords: Scorpion toxins, venom peptides, ion channels, non-disulfide-bridged peptides, disulfide-bridged peptides, buthidae, chaerilidae. 1. INTRODUCTION

Scorpions are the exclusive arachnids in many ways. Around 430 million years ago, the scorpions appeared and evolved as very complex animals [1]. Over 1500 species of scorpions have been defined so far around the world [2]. The biggest genome to be sequenced among the Arthropoda is that of the scorpion with almost 32,016 genes coding the proteins, 800 well-characterized active polypeptides along with the stabilized structures [3-5]. These arthropods have been categorized in two groups alongside their geographical distribution. The unique distribution of scorpion venom system is an evidence for the independent evolution among the venomous animals as they have the gland of venom, whose position is on the tip of the stinger preceding the tail [6]. Venoms have progressed on frequent events through the visceral territory. These “natural weapon system” functions *Address correspondence to this author at the Faculty of Pharmacy, University of Central Punjab, Lahore, Pakistan; Tel: +00923332322200; E-mail: [email protected] 1875-5305/18 $58.00+.00

against predation. Despite molecular evolution, efficient merging, interactions among prey and predators, pharmacological discoveries; the animal with venoms is mostly unstudied. Generally, the peptides of scorpion venom belong to Disulfide-bridged Peptides (DBPs) and the Non-disulphide Bridged Peptides (NDBPs) both involved in multi-functional activities [7]. This might be a promising platform for the development of new drugs; thus, the growing importance of scorpion derivatives reviewed and reported in this article. 2. SCORPION VENOM Scorpion venom is a mixture of lipids, nucleotides, amines, polypeptides and other unidentified constituents [8]. The amount of venom produced depends on the number of stings and the specimen. The amount of peptide contained in the venoms must not exceed 5% of the total dried weight and thus it contains polypeptides with different structures, target sites, functions and toxicities for other organisms [9]. When compared to spiders and snake venoms, the scorpion venoms show a lower level of enzyme activity and hold phospholi-

© 2018 Bentham Science Publishers

Editor-in-Chief:

Ben M. Dunn

Scorpion Venom Peptides as a Potential Source for Human Drug Candidates

Protein & Peptide Letters, 2018, Vol. 25, No. 7

703

pases, inhibitors of proteases and other low molecular weight molecules. Examples are neurotoxic peptides, which interact with the membrane receptors or with the ion channels and activating the components via cytosolic interface. Scorpion venom peptides may also specifically bind to the cancer cells. Thus, venom holds the molecules of interest that may be featured for the clinical usefulness, drug design and development [8, 10, 11].


Due to the pharmacological aspects and significance, the toxins of scorpion venoms are the most studied and are most relevant as they have a significant effect on human beings and can be categorized into α -toxins and β - toxins. Specifically, α -toxins are involved in the delayed inactivation of voltage gated Na+ channel while the β-toxins are involved in the opening of these channels with a more negative potential [12]. A decrease in excitability along with depolarization of cell membrane is followed in the cases with low doses of αtoxins whereas in higher doses, the stroke possibility of excitable cells prolongs, thus inducing paralysis and cardiac arrhythmia [13, 14]. The actions of β-toxins provoke the paralytic muscular spastic responses [11, 15]. Toxins of the scorpion venom are identified for their poisonous effects on organisms (cells and tissues) but in contrast to that, these venoms have shown significant potential for drug development and pharmaceuticals. 3. CLASSIFICATION 3.1. DBPS Toxins

The DBPs consists of 3-4 disulphide bridges and are the ones affecting the Na+, K+, Ca++ and Cl- channels and are usually pleated with stabilized cysteine motifs [1]. 3.1.1. Toxins of Na+ Channel

Na+ channel scorpion toxins (NaTxs) consists of 58-76 amino acids interconnected by 3-4 disulphide bonds. On the base of these binding properties, Natxs have been grouped in two categories: α-Natxs and β-Natxs. The 3-D conformation of these peptides comprises of structural core with 6 cysteine along with three conserved disulphide bridges while the fourth one can have three different arrangements [1]. Until now, 14 such toxins are known from 6 scorpion species [16]. These are the long chain peptides with the neurotoxic effects during the envenomation through scorpion [1]. In another study, the molecular model for the Bukatoxins was revealed showing the site for the binding and interaction (Figure 1A). Where, in Figure 1B, Asp9 and Val I is also taking part for the recognition and surface interactions [17]. 3.1.2. Toxins of K+ Channel Scorpion venoms are a rich source for the specific toxins of K+ channel and can be used for the functional and structural classification of K+ channel. The length of toxics acting on K+ channel varies between 23 to 64 amino acids with a molecular weight of approximately 4000 Da. They are further classified on their primary amino acid sequences and the cysteine pairing [18, 19] into four families α -, β -, γ - and κKTx. These peptides interact in two ways to the K + channels; the pore plug-in mode and the transitional mode (inter-

Figure 1. A: The molecular model for the Bukatoxin; B: Surface of Bukatoxin which interacts with Na+ channel.

mediate mode) where binding is stabilized and assisted by the negatively charged loop of KCa2+ channels when comes in contact with the basic residues of toxins [12, 19].

Peptides of this family are also known as Ergtoxins as they exhibit the character of blocking the ERG-K+ channels of the nerves, the heart and the endocrine cells [1]. A most recent study also discusses the new peptide isolation carried from a Mexican scorpion with the structures primarily determined and provide implementation for the structure and function-based relationship of K + channel blocking toxins of scorpion [20]. 3.1.3. Toxins of Cl- Channel Although there exist some structural similarities between the chlorotoxins and the Ktx toxins, the peptides of this family are about ~30-40 amino acid residues following the formation of the disulphide bridges [1, 21]. Some studies also elucidate that some toxins employ an excess of pharmacological effects but still the present classification of toxins need to be revised [1].

704 Protein & Peptide Letters, 2018, Vol. 25, No. 7

Uzair et al.

and the therapeutic importance of scorpion venom. The proteomic and transcriptomic analysis led to the discovery of new-type venom peptides with the distinctive features of venom peptides from the A. bicolor specie. The data suggests the use of novel templates of peptides for the drug development, ion channels related diseases, and other toxicities that occur due to the pathogenic effects of antibiotic resistance [16].

3.2. NDBPs Toxins Smaller groups of the scorpion venom peptides display multi-biological functions including the antiviral, antimalarial, anti-cancer, anti-inflammatory, bradykinin potentiating functions [7]. The scorpion NDBPs toxins comprise of 13-56 amino acids and approximately 40 peptides have been functionally characterized so far. Except for peptide T, peptides show the α-helical structures and are further classified into three classes. The presence of unordered coiled confirmation is seen in aqueous conditions [7, 10]. Figure 2 shows the proportions of some anti-microbial peptides [22].

To obtain an overview of evolution among venom peptides derived from different venom of different scorpion species, Phylogeny.fr software was used. The species were selected from Pandinus imperator (Scorpion), Chaerilus tricostatus, Buthus martensii, Mesobuthus eupeus, Leiurus quinnquestriatus, Tityus discrepans and Heterometrus bengalensis. The results of evolution are shown in Figures 3 and 4; i.e., showing the cladogram and the circular tree for the venom peptides.

4. DIVERSITY OF VENOM PEPTIDES Venom components are being explored for the traditional therapeutic discovery projects since 1940’s with the use of tubocurarine (basic component of curare, i.e., the South American arrow poison) [23]. In a recent study, one of the most poisonous species of scorpion, namely Androctonus bicolor; was used for understanding the molecular diversity


Another study conducted in 2013, elucidates that one of the scorpion family, namely Chaerilidae, is phylogenetically different from the Buthidae (containing NaTx, β -KTx, BPP and Scamp peptides). Its venom compositions are not known

Na+ channel

channel 30-40 amino acids Cl-

58-76 aminio acids 3-4 disulphide bonds

K+ channel 23-64 amino acids

NDBP's 13- 56 amino acids

Na+ channel

K+ channel

Cl- channel

NDBP's

Figure 2. Classification of peptides based on amino acid composition.

AAK57517.0_defensin-like_protein_TXKS2_Mesobuthus_martensii 0.44

0.23

0.78

0.73

ADR83705.1_neurotoxin_Bmk_partial_Mesobuthus_martensii AAZ29711.1_putative_neurotoxin_Td4.2_precursor_partial_Tityus_di

0.45

aILQI_A_Chain_A_Insecticidal_Alpha_Scorpion_Toxin_Isolated_from aIZUT_A_Chain_A_Crystal_Structure_Of_Mutant_K8dp9sr58k_Of_Scorpion POCCI1.1_RecName_Full=Bengalin

0 0.36

POCH58.1_RecName_Full=Meucin-25_AltName_Full=BeL-170_AltName_Ful AEK32596.1_antimicrobial_peptide_riporin_Chaeritus_tricostatus

0.23

CAB96789.1_scorpion_defensin_Pandinus_imperator n2KFE_A_Chain_A_Solution_Structure_Of_Meucin-24

Figure 3. The evolutionary analysis of Scorpion venom peptides.


AD

n2

AAK57517.1

KF EA

Ch

so far as well the evolution is not well assumed. Although, the Chaerilidae family of scorpion (including Tityus discrepans and Lychas mucronatus) have specific venom arsenal with high AMP and lower neurotoxin expressions and is an intermediate between the Buthidae and the non-Buthidae species, i.e., Hadrurus gertschi, H. petersii and S. Jendeki, hence, suggesting an evolution of the venom components [24]. Figure 5 shows comparison between Buthidae, Chaerilidae and non-Buthidae family for toxins.

R8 37

.1

6789

Ch

AEK

ZU

TA

3259

6.1

.1

58

CH

P0

P0CC11.1 R

n1

5. VENOM TOXINS CONJUGATED NANOPARTICLES Nano-medicinal tactics for the drug development gained much fascination to develop a drug based on nanoparticle conjugated with the biomolecules for the enhanced efficacy. Venom toxins are one of the emerging category with the higher medicinal values and targeted deliveries when conjugated with the nanoparticles against the emerging diseases [25]. However, the issue with the use of immune-adjuvants for serum and vaccines involves the toxicity and the side effects. A study on chitosan nanoparticles with conjunction of peptides derived from the scorpion venom of specie T. serrulatus shows chitosan nanoparticles, as immuneadjuvants with target specific system of delivery [26]. The use of hydrophilic nanoparticles has also been investigated for the targeted delivery of macromolecules. Another study revealed the use of chitosan nanoparticles loaded with the venom peptides of Mesobuthus eupeus as a suitable substitute for the traditional adjuvant method [27]. 6. ANTI-MICROBIAL PEPTIDES (AMPS) FROM SCORPION VENOM

h

IAC

n1LQ

705

Pe N rs ot on fo al rD U is se tri O bu n tio ly n 9 CAB

.1

2971 1.1

05

AAZ


R

Figure 4. The circular phylogenetic tree of scorpion venom peptides.

Buthidae

(NaTx, b-KTx, bpp and Scamp)

Chaerilidae High AMP and low neurotoxin (acts as intermediate)

Non buthidae

The necessity of novel antimicrobial agents is becoming one of the prerequisites in the modern medicines due to resistant pathogenic microorganisms. The scorpion venoms are one of the leading source of the therapeutic agents together with the antimicrobial peptides (Table 1) [22]. AMPs are derived from a variety of plants and animals among those scorpions have a unique significance [9]. Bactridines arises as prospective research tools to comprehend the sodium channel isoform configuration and functional associations and as well pharmacologically stimulating peptides [28]. Various peptides from the scorpion venom have been isolated containing the cysteine residues, i.e. the Non Disulphide Bridged Peptides (NDBP’s), [29] and have been characterized in further three classes. Some AMPs function while disrupting the cell (cell membranes) via different mode of actions. Along with the cell membrane disruption, the effects of scorpion toxins can be intermediated via ion channels while some AMPs block the microbial growths via phospholipase activity [9]. One of the scorpion venom NDBPs component, namely Ctriporin, displays the antimicrobial properties which contains 19 amino acids and have a potential against the grampositive strains and as well as involved in the inhibition of the growth of the pathogens such as MRSA, PRSE, i.e., which are resistant to antibiotics [11]. For MRSA, Ctriporin has the potential to treat the skin infections related to MRSA [10]. Scorpine from the Pandinus imperator species was found to be effective against gram positive and gramnegative bacteria and it exhibited anti-malarial properties [22]. Two more peptides from Buthus martensii BmKb1 and BmKb2 showed activity against gram positive and against gram-negative organisms, respectively. The BmKb2 also showed activity against the strains of N. gonorrheae [30,22]. 7. ANTI-MALARIAL PEPTIDES FROM SCORPION VENOM

Figure 5. The Evolution of Scorpion Venoms and Comparison between Buthidae, Chaerilidae and non-Buthidae family for toxins.

Malaria poses to be one of the endemic disease among hundreds of the tropical countries. However, morbidity and


Table 1.

Uzair et al.

Activities of Anti-microbial peptides derived from Scorpion venom.

Antimicrobial Peptides

Source Specie

Therapeutic Role

References

Scorpine or Panscorpine (KBX3_PANIM)

Pandinus imperator (Scorpionidae)

Against both gram-positive and gram-negative bacteria and parasites (K. pneumonia & B. subtilis)

[22]

Ctriporin

Chaerilus tricostatus

Against Gram - positive bacteria and pathogens, skin infections

[10]

BmTXKS2 (BmKb1 & BmKb2)

Buthus martensii

Against N. gonorrhoeae

[30]

Table 2.

Anti-malarial activities of Meucin 24 and Meucin 25 peptides derived from scorpion venom. Source Specie

Therapeutic Role

References

Meucin 24

Mesobuthus eupeus (lesser Asian scorpion)

Inhibitory effects towards malaria

[10, 11]

Meucin 25

Mesobuthus eupeus (lesser Asian scorpion)

Inhibitory effects towards malaria

[10, 11]

Table 3.


Anti-malarial Peptides

The activities of some anti-viral peptides derived from Scorpion venom. Anti-viral Peptides

Activity

References

Cationic Alpha particles

Antiviral drugs development

[31]

Hp1090

Interaction with viral particles

[10]

Human monoclonal antibodies (mAb hu2c)

Defends against the viral spread

[33]

mortality has decreased in past years, yet the death rate caused by the Anopheles mosquito reaches up to 2000, yearly. Scorpion peptides were the first to show the inhibitory effects on malarial stages. Meucin 24 and Meucin 25 were identified for the first time from NDBPs of scorpions showing the selective antimalarial activity with no toxicity against the P. falciparum (Table 2). A reduction in the density of intra erythrocytic P. falciparum was observed at 48 h post examination [10, 11].

eases. Two venom peptides are known to have inhibitory effect on HSV-I and thus known as a candidate for the development of viricides [32]. Human monoclonal antibodies (mAb hu2c) were developed and are known to annul completely the viral spread from cell to cell which is a fundamental method through which HSV I or HSV-II outflows the humoral immune observations [33].

8. ANTI-VIRAL VENOM

Scorpion toxins are one of the most promising approaches to combat cancer, both in vitro and in vivo, as well in the clinical manifestations. Cationic alpha helical peptides are one of the bioactive peptides for the anticancer activities. ACPs are basically small peptides with below 50 amino acids and the peptides exhibits the property to adopt the hydrophobic nature along with the α-helical secondary structure which allows the peptides to bend in amphiphilic pattern once in contact with membranes. ACPs show a distinguishing structural and morphological characteristic against the cancer cells [10]. Chlorotoxins (cltx) are one of the eminent peptides derived from the scorpion specie Leiurus quinnquestriatus with 36 amino acids and functions for the inhibition of the chloride invading the glioma cells. This toxin binds to the Matrix Metalloproteinase II (MMP-II), expressed by the glioma cells there by losing the gelatinase activity [8]. Another study explains the activity of two novel peptides, i.e. neopladine I and neopladine II, derived from Tityus discrepans species of the scorpions. These peptides showed activity against the human breast carcinoma SKBR3 cells. The study showed both neopladines have a major

PEPTIDES

FROM

SCORPION

Viral diseases emerging represent a major threat to human morbidity and mortality globally. Vaccination has been a supporting strategy to manage and eradicate a number of pathogens, but a large number of viral infections are still threats with no vaccines available for treatment. Thus, new strategies were essential for the manufacture of therapeutic agents to manage viral infections. A study revealed the cationic alpha particles with potential as antiviral carriers and minimal side effects [31]. Hp 1090 was the first NDBP comprising of 13 amino acids with the potential to directly interact with the viral particles of HCV when compared to IFN-α [10]. Table 3 shows the activities of some ant-viral peptides derived from scorpion venom. 9. HERPES SIMPLEX VIRUS TYPE I Herpes Simplex Virus type I (HSV-I) is a widespread human pathogen infecting the epithelial tissues leading to formation of lesions in oral mucosa and other severe dis-

10. ANTI-CANCER PEPTIDES (ACPS) FROM SCORPION VENOM


Table 4.


707

Anticancer peptides derived from Scorpion venom toxins.

Anti-cancerous Peptides

Source Specie

Therapeutic Role

References

ACP’s

-

Characters against cancer cells

[10]

Chlorotoxins (cltx)

Leiurus quinnquestriatus

Inhibition of chloride invading the glioma cells

[8]

Neopladine I

Tityus discrepans

Active against human breast carcinoma SKBR3 cells

[34]

Neopladine II

Tityus discrepans

Apoptic action deprived of necrosis

[34]

BmK

Buthus martensii

Pain relieving effects FOR gut and somatic pains

[30]

BmK AGAP-SYPU2

Buthus martensii

Reduction in tumor weight and prolonged survival

[30]

All components

Heterometrus bengalensis

Anti-proliferative and apoptogenic activities

[11]

activities of scorpion peptides. The studies conducted with the animal toxins are contributing effectively towards the advancement in biomedical science, as it is evident that several biologically active molecules present many pharmaceutical applications. The observations confirm that peptides conjugated with the venom toxins exhibit improved therapeutic effects of the drugs. In short, nature remains the ultimate answer to many health issues, which need to be solved. Possibly using the nanoparticles may offer alternate to adjuvant system and for the site-specific targeting. For this, venom toxins conjugated with nanoparticles could offer revival in medical science especially in drug development. Furthermore, the comprehensive characterization of peptides from different scorpions is very much necessary to define actual biological potential. The venom of different scorpion species so far has proved to be rich sources of anti-microbial, anti-malarial, anti-cancerous, anti-bacterial and anti-viral actives. The detailed study for the toxicity profile and bioavailability must be considered to establish the role of venoms in future drug development.


apoptic action deprived of necrosis [34]. BmK AGAPSYPU2 display strong pain-relieving effects against the gut and the somatic pains and also exhibits high sequence homology with the α-toxins. BmK AGAP-SYPU2 also showed anti-tumor activity with the prolongation in the survival (36.05%) while a reduction in tumor weight by 46.3% [30]. The components of Heterometrus bengalensis exhibited the anti-proliferative and apoptogenic activities on the human cell lines for leukemia (U937 and K562) [11]. Table 4 shows anticancer peptides derived from Scorpion venom. 11. OSTEOPOROSIS

The venom of the scorpion Heterometrus bengalensis exhibited remarkable anti-osteoporosis effects in a study conducted in ovariectomized rats. The venom also increased minerals deposits in the bones [9]. Another study using the Indian red scorpion venom suggested that the scorpion venom produced the analgesic affects thus the results leading to the confirmation of the anti-arthritic activities as well leading to the alterations in the arthritic conditions [35].

LIST OF ABBREVIATIONS

12. HOMEOSTATIC AND RHEOLOGICAL ACTIVITY

Fascinatingly, a number of components of the venom are required for the injuries related to the blood and rheology while the toxic effects of envenomation through the scorpion venom. Directly or indirectly, effects the neurotoxins leading to the changes in the hemodynamic and cardiovascular functions. The scorpion venom is one of the most remarkable for the improved blood rheology and homeostasis within the Chinese ethno medicine. The study proposed that the components of scorpion venom could be used for the aggregates of platelets [9]. Another approach to the use of scorpion venom peptides is for the regulation of blood known as angiokinesis. A study conducted provides the details about the cardiovascular drug using the venom peptides from the scorpions. They suggested that the Bradykinin peptides from the scorpion lead to the inhibition of the angiotensin II resulting in the decreased blood flow [5]. CONCLUSION An overview of composition of different scorpion venoms is presented along with the biological analysis of the

AMPs

=

Anti-Microbial Peptides

BPP

=

Bradykinin Potentiating Peptides

cltx

=

Chlorotoxins

DBPs

=

Disulfide-Bridged Peptides

HCV

=

Hepatitis C Virus

IFNα

=

Interferon Alfa

MRSA

=

Methicillin-Resistant Staphylococcus aureus

NaTxs

=

Na+ Channel Scorpion Toxins

NDBPs

=

Non-Disulfide-Bridged Peptides

PRSE

=

Penicillin-Resistant Staphylococcus epidermidis

CONSENT FOR PUBLICATION Not applicable.


Uzair et al.

CONFLICT OF INTEREST

[19]

The authors declare no conflict of interest, financial or otherwise.

[20]

ACKNOWLEDGEMENTS Declared none.

[21]

REFERENCES

[2] [3] [4] [5] [6]

[7] [8] [9] [10]

[11] [12] [13] [14]

[15]

[16]

[17]

[18]

Santibáñez-López, C.E.; Possani, L.D. Overview of the Knottin scorpion toxin-like peptides in scorpion venoms: Insights on their classification and evolution. Toxicon, 2015, 107(Pt B), 317-326. Hmed, B.; Serria, H.T.; Mounir, Z.K. Scorpion peptides: potential use for new drug development. J. Toxicol., 2013, 2013, 958797. Bailey, P.; Wilce, J. Venom as a source of useful biologically active molecules. Emerg. Med. (Fremantle), 2001, 13(1), 28-36. Bawaskar, H.S. Can scorpions be useful? Lancet, 2007, 370(9599), 1664. Hodgson, W.C.; Isbister, G.K. The application of toxins and venoms to cardiovascular drug discovery. Curr. Opin. Pharmacol., 2009, 9(2), 173-176. Ma, Y.; He, Y.; Zhao, R.; Wu, Y.; Li, W.; Cao, Z. Extreme diversity of scorpion venom peptides and proteins revealed by transcriptomic analysis: implication for proteome evolution of scorpion venom arsenal. J. Proteomics, 2012, 75(5), 1563-1576. Almaaytah, A.; Albalas, Q. Scorpion venom peptides with no disulfide bridges: a review. Peptides, 2014, 51, 35-45. Heinen, T.E.; da Veiga, A.B.G. Arthropod venoms and cancer. Toxicon, 2011, 57(4), 497-511. Hmed, B.; Serria, H.T.; Mounir, Z.K. Scorpion peptides: potential use for new drug development. J. Toxicol., 2013, 2013, 1-15. Almaaytah, A.; Tarazi, S.; Mhaidat, N.; Al-Balas, Q.; Mukattash, T.L. Mauriporin, a novel cationic α-helical peptide with selective cytotoxic activity against prostate cancer cell lines from the venom of the scorpion Androctonus mauritanicus. Int. J. Pept. Res. Ther., 2013, 19(4), 281-293. Ortiz, E.; Gurrola, G.B.; Schwartz, E.F.; Possani, L.D. Scorpion venom components as potential candidates for drug development. Toxicon, 2015, 93, 125-135. Rodríguez de la Vega, R.C.; Schwartz, E.F.; Possani, L.D. Mining on scorpion venom biodiversity. Toxicon, 2010, 56(7), 1155-1161. Chippaux, J.P. Emerging options for the management of scorpion stings. Drug Des. Devel. Ther., 2012, 6, 165-173. Bosmans, F.; Tytgat, J. Sea anemone venom as a source of insecticidal peptides acting on voltage-gated Na+ channels. Toxicon., 2007, 49(4), 550–560. Diego-García, E.; Caliskan, F.; Tytgat, J. The Mediterranean scorpion Mesobuthus gibbosus (Scorpiones, Buthidae): transcriptome analysis and organization of the genome encoding chlorotoxin-like peptides. BMC Genomics, 2014, 15(1), 295. Zhang, L.; Shi, W.; Zeng, X.C.; Ge, F.; Yang, M.; Nie, Y.E.G. Unique diversity of the venom peptides from the scorpion revealed by transcriptomic and proteomic analysis. J. Proteomics, 2015, 128, 231-250. Srinivasan, K.N.; Nirthanan, S.; Sasaki, T.; Sato, K.; Cheng, B.; Gwee, M.C.E.; Kini, R.M.; Gopalakrishnakone, P. Functional site of bukatoxin, an α-type sodium channel neurotoxin from the Chinese scorpion (Buthus martensi Karsch) venom: probable role of the (52)PDKVP(56) loop. FEBS Lett., 2001, 494(3), 145-149. Bergeron, Z.L.; Bingham, J.P. Scorpion toxins specific for potassium (K+) channels: a historical overview of peptide bioengineering. Toxins (Basel), 2012, 4(11), 1082-1119.

[22]

[23] [24]

[25]


[1]

Quintero-Hernández, V.; Jiménez-Vargas, J.M.; Gurrola, G.B.; Valdivia, H.H.; Possani, L.D. Scorpion venom components that affect ion-channels function. Toxicon, 2013, 76, 328-342. Olamendi-Portugal, T.; Bartok, A.; Zamudio-Zuñiga, F.; Balajthy, A.; Becerril, B.; Panyi, G.; Possani, L.D. Isolation, chemical and functional characterization of several new K(+)-channel blocking peptides from the venom of the scorpion Centruroides tecomanus. Toxicon, 2016, 115, 1-12. Mohammadpour Dounighi, N.; Eskandari, R.; Avadi, M.R.; Zolfagharian, H.; Mir Mohammad Sadeghi, A.; Rezayat, M. Preparation and in vitro characterization of chitosan nanoparticles containing Mesobuthus eupeus scorpion venom as an antigen delivery system. J. Venom. Anim. Toxins Incl. Trop. Dis., 2012, 18(1), 4452. Harrison, P.L.; Abdel-Rahman, M.A.; Miller, K.; Strong, P.N. Antimicrobial peptides from scorpion venoms. Toxicon, 2014, 88, 115-137. Harvey, A.L. Toxins and drug discovery. Toxicon, 2014, 92, 193200. He, Y.; Zhao, R.; Di, Z.; Li, Z.; Xu, X.; Hong, W.; Wu, Y.; Zhao, H.; Li, W.; Cao, Z. Molecular diversity of Chaerilidae venom peptides reveals the dynamic evolution of scorpion venom components from Buthidae to non-Buthidae. J. Proteomics, 2013, 89, 1-14. Biswas, A.; Gomes, A.; Sengupta, J.; Datta, P.; Singha, S.; Dasgupta, A.K.; Gomes, A. Nanoparticle-conjugated animal venomtoxins and their possible therapeutic potential. J. Venom Res., 2012, 3, 15-21. Soares, K.R.S.; Fonseca, J.C.L.; Bitencourt, M.O.A.; Santos, K.S.C.R.; Silva-Júnior, A.A.; Fernandes-Pedrosa, M.F. Serum production against scorpion venom using cross-linked chitosan nanoparticles as immunoadjuvant. Toxicon, 2016, 60(8), 13491354. Dupré, G. Conspectus genericus scorpionorum 1758–2006 (Arachnida: Scorpiones). Euscorpius, 2007, 50, 1-31. Peigneur, S.; Sevcik, C.; Tytgat, J.; Castillo, C.; D’Suze, G. Subtype specificity interaction of bactridines with mammalian, insect and bacterial sodium channels under voltage clamp conditions. FEBS J., 2012, 279(21), 4025-4038. Zeng, X.C.; Zhou, L.; Shi, W.; Luo, X.; Zhang, L.; Nie, Y.; Wang, J.; Wu, S.; Cao, B.; Cao, H. Three new antimicrobial peptides from the scorpion Pandinus imperator. Peptides, 2013, 45, 28-34. Shaoa.; Yong, Cuia.; Ming-Yi, Zhao.; Chun-Fu, Wu.; Yan-Feng, Liu.; Jing-Hai, Zhang.Purification, characterization, and bioactivity of a new analgesic-antitumor peptide from Chinese scorpion Buthusmartensii Karsch. Peptides, 2014, 53, 89-96. Thakur, N.; Qureshi, A.; Kumar, M. AVPpred: collection and prediction of highly effective antiviral peptides. Nucleic Acids Res., 2012, 40(Web Server issue), W199-204. Hong, W.; Li, T.; Song, Y.; Zhang, R.; Zeng, Z.; Han, S.; Zhang, X.; Wu, Y.; Li, W.; Cao, Z. Inhibitory activity and mechanism of two scorpion venom peptides against herpes simplex virus type 1. Antiviral Res., 2014, 102, 1-10. Krawczyk, A.; Arndt, M.A.; Grosse-Hovest, L.; Weichert, W.; Giebel, B.; Dittmer, U.; Hengel, H.; Jäger, D.; Schneweis, K.E.; Eis-Hübinger, A.M.; Roggendorf, M.; Krauss, J. Overcoming drugresistant herpes simplex virus (HSV) infection by a humanized antibody. Proc. Natl. Acad. Sci. USA, 2013, 110(17), 6760-6765. D’Suze, G.; Rosales, A.; Salazar, V.; Sevcik, C. Apoptogenic peptides from Tityus discrepans scorpion venom acting against the SKBR3 breast cancer cell line. Toxicon, 2010, 56(8), 1497-1505. Nipate, S.; Soni, V.B.; Ghaisas, M.M. Anti-arthritic effect of Indian red Scorpion (Mesobuthus tamulus) venom in Freund’s complete Adjuvant and collagen type II induced arthritis. J. Clin. Toxicol., 2014, 4, 192.

[26]

[27]

[28]

[29]

[30]

[31] [32]

[33]

[34] [35]