Cordeiro et al.

Journal of Venomous Animals and Toxins

including Tropical Diseases (2015) 21:24
DOI 10.1186/s40409-015-0028-5

REVIEW Open Access

Arachnids of medical importance in Brazil:

main active compounds present in
scorpion and spider venoms and tick saliva
Francielle A. Cordeiro, Fernanda G. Amorim, Fernando A. P. Anjolette and Eliane C. Arantes*

Abstract
Arachnida is the largest class among the arthropods, constituting over 60,000 described species (spiders, mites,
ticks, scorpions, palpigrades, pseudoscorpions, solpugids and harvestmen). Many accidents are caused by
arachnids, especially spiders and scorpions, while some diseases can be transmitted by mites and ticks. These
animals are widely dispersed in urban centers due to the large availability of shelter and food, increasing the
incidence of accidents. Several protein and non-protein compounds present in the venom and saliva of these
animals are responsible for symptoms observed in envenoming, exhibiting neurotoxic, dermonecrotic and
hemorrhagic activities. The phylogenomic analysis from the complementary DNA of single-copy nuclear
protein-coding genes shows that these animals share some common protein families known as neurotoxins,
defensins, hyaluronidase, antimicrobial peptides, phospholipases and proteinases. This indicates that the
venoms from these animals may present components with functional and structural similarities. Therefore, we
described in this review the main components present in spider and scorpion venom as well as in tick saliva,
since they have similar components. These three arachnids are responsible for many accidents of medical
relevance in Brazil. Additionally, this study shows potential biotechnological applications of some components
with important biological activities, which may motivate the conducting of further research studies on their
action mechanisms.
Keywords: Arachnid toxins, Scorpion venom, Spider venom, Tick saliva

Background review will focus on the main Brazilian venomous animals

Envenomings are considered a neglected disease by the of the Arachnida class belonging to Scorpionida, Araneae,
World Health Organization [1] and constitute a public Ixodidae orders as well as on the aspects related to enve-
health problem, especially in tropical countries. The ani- noming caused by these animals and their venom/saliva
mals responsible for such accidents possess an apparatus composition, highlighting the components of scientific
associated with a venom gland that is able to produce and medical interest.
a mixture rich in toxic and nontoxic components [2]. The phylogenomic analysis of the nuclear protein-coding
Among the most studied arthropod venoms are those sequences from arthropod species suggests a common
from scorpions, spiders and ticks, belonging to the origin in the venom systems of scorpions, spiders and
phylum Arthropoda, class Arachnida, which correspond to ticks [5, 6]. Specifically, catabolite activator protein (CAP),
the purpose of this review. They are widely dispersed in defensins, hyaluronidase, Kunitz-like peptides (serine pro-
urban centers due to the large availability of shelter and teinase inhibitor), neurotoxins, lectins and phospholipase
food, which facilitates their reproduction and consequently are examples of compounds shared by these animals (Fig. 1).
increases the number of accidents [3, 4]. Therefore, this Some compounds such as alanine-valine-isoleucine-threo-
nine protein (AVIT protein) and sphingomyelinase have
* Correspondence: ecabraga@fcfrp.usp.br
been identified in spiders and ticks. Cystatins, lipocalins
Department of Physics and Chemistry, School of Pharmaceutical Sciences of and peptidase S1 are found only in ticks [5].
Ribeirão Preto, University of São Paulo (USP), Avenida do Café, s/n, Ribeirão
Preto, SP 14.040-903, Brazil

© 2015 Cordeiro et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://
creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Cordeiro et al. Journal of Venomous Animals and Toxins including Tropical Diseases (2015) 21:24 Page 2 of 14

The scorpion venom apparatus consists of a gland

connected to a telson sting which is located on the last
segment of the post-abdomen of the animal (Fig. 2). This
is an apparatus of great importance for their survival,
assisting in feeding and self-defense of the scorpion. The
telson has a vesicle that contains a pair of glands respon-
sible for the production and storage of the venom [2].
A scorpion sting is characterized by intense pain and
systemic symptoms that usually develop rapidly [10]. Ac-
Fig. 1 Venn diagram highlighting the protein families presented in cording to clinical manifestations, scorpion envenomings
tick saliva and scorpion/spider venoms. Catabolite activator protein are classified as mild, moderate or severe. The general
(CAP), defensins, hyaluronidase, Kunitz-like peptides (serine proteinase initial response to a scorpion sting is immediate local
inhibitor), neurotoxins, lectins and phospholipase are some of the
compounds shared among these arthropods
burning pain, which may be severe. General symptoms
may occur soon after the sting, but may be delayed for
several hours. Therefore, vital functions of patients with
In this context, the study of the structural similarity systemic manifestations should be observed continuously,
among these compounds/toxins identified in the venom/ while seeking early treatment of the complications [11].
saliva of these animals may contribute to a better under- So far, approximately 2,000 species of scorpions have
standing of the action mechanism involved in envenoming been described, distributed worldwide. These arach-
besides providing information about molecules with great nids are classified into seven families: Scorpionidae,
biotechnological potential. Diplocentridae, Chactidae, Vaejovidae, Bothriuridae,
Chaerilidae and Buthidae. The most dangerous species
belong to the family Buthidae, which comprises more
Review than 500 species. In Brazil the scorpions with the
Scorpion venoms highest medical and scientific interest belong to the
Scorpion envenoming is considered a public health prob- genus Tityus [2, 12–15].
lem, especially in tropical countries [7]. Annually, more There are more than ten different Tityus species in
than one million cases of scorpion envenomation are Brazil, among which Tityus stigmurus, Tityus bahiensis
reported worldwide with a fatality risk of around 3 % and Tityus serrulatus are primarily responsible for hu-
[8]. According to the data from the Brazilian Ministry man envenoming. T. serrulatus is considered the most
of Health, 57,933 accidents were recorded in Brazil in dangerous species in the country, responsible for the
2011, of which 91 cases resulted in death [9]. highest number of envenoming accidents [16, 17].

Fig. 2 Photo of a scorpion and schematic representation of scorpions’ telson. Morphology of the inoculum apparatus of scorpion venom located
on the last segment of the post-abdomen of the animal. The telson comprises a pair of glands responsible for the production and storage of the
venom used for feeding and self-defense of the scorpion
Cordeiro et al. Journal of Venomous Animals and Toxins including Tropical Diseases (2015) 21:24 Page 3 of 14

Biochemical characteristics of the venom from Tityus The α-NaScTx retards the mechanism of Nav inactivation
Scorpion venoms are a complex mixture of substances and prolongs the repolarization phase of the membrane
that include: inorganic salts, free amino acids, heterocyclic action potential [2]. The α-NaScTx can be subdivided into
components, peptides and proteins, mainly enzymes that the following three main groups: (1) classical α-toxins,
are used by the scorpions for self-defense and the capture which are highly active only in mammalian Nav channels
of prey [18]. A broad range of bioactive compounds of and present poor toxicity against insects; (2) anti-insect α-
scorpion venoms have already been purified and char- NaScTXs, which are highly active only on insect Nav
acterized. It is estimated that the number of different channels; and (3) α-like toxins, active on both insect and
components present in these venoms is approximately mammalian Nav channels [18]. As shown in Table 1,
100,000, but only 1 % of these molecules have been iso- toxins such as Ts3 isolated from T. serrulatus, TbTx5 from
lated and characterized [19]. The advent of recombin- T. bahiensis and Tst3 from T. stigmurus are highly con-
ant DNA technology, such as transcriptome analysis, served between the species sharing a high percentage of
allowed the identification of new components; however, identity [29–31]. Those toxins also show high similarity
some of them have not yet been directly purified from with Ts5 of T. serrulatus and Tb3 of T. bahiensis. The Ts3
the venom. relaxes the human corpus cavernosum in vitro through
Venoms varies compositionally from genus to genus and the release of NO from nitrergic nerves and the elucida-
species to species and may differ in potency, probably due tion of its action mechanism would be useful for the de-
to changes in the proportion of their toxins, associated with velopment of new therapeutic strategies to treat priapism
genetic and environmental variations, such as diet and cli- after scorpion envenomation. Additionally, this is a mol-
mate [20–23]. Studies have shown that T. serrulatus venom ecule that can be used as a model for the development of
is two to three times more toxic than that of T. bahiensis, a new drug to treat erectile dysfunction [32].
which explains the various studies that aimed to isolate and Another class of toxins that affect Nav channels is the
characterize their toxins [2]. Furthermore, such studies β-neurotoxins (β-NaScTx), which bind to receptor site 4
found variability in venom lethality among T. serrulatus in the extracellular loops that connect transmembrane
specimens, which suggests that neurotoxins, such as α-type segments S3 and S4 and the S1 and S2 segments in domain
neurotoxin, must be the major lethal component in the II [2, 18]. Thus, this class alters the voltage-dependence of
whole venom [24]. channel activation to more negative potentials to cause an
The major components of scorpion venom are neuro- increased tendency to trigger the spontaneous and the
toxins, which act on ion channels of excitable cells [25]. repetitive potentials of the membrane [2]. Similar to α-
The venom compounds may interact with each other to NaScTx, the β-neurotoxins are subdivided into four
modulate the function of ion channels, which is usually groups according to their pharmacological selectivity
responsible for the known symptoms of envenoming. for insect and mammalian Nav channels: (1) βm, active
Scorpion neurotoxins present a tightly tridimensional- on mammalian Nav channels; (2) βi, selectively active
shaped backbone stabilized by three or four disulfide on insect Nav channels; (3) β-like, for toxins without
bridges. This property avoids their in-vivo degradation, preference between mammalian and insect Nav chan-
thereby increasing their interaction time with ion channels nels and (4) βα, for those that presents a primary structure
and their efficacy [18]. of β-toxins, but with a functional α-effect [14]. The
Four different families of neurotoxins are usually found toxin Ts1, a β-neurotoxin with action on Nav channels,
in scorpion venom: peptides that modulate sodium-, is the most abundant toxin in T. serrulatus venom,
potassium-, chloride- or calcium-gated channels [12]. The whose activities include inducing macrophage activation
most studied families of venom neurotoxins from Tityus in vitro [33, 34].
species act on sodium and potassium channels. The poorly The neurotoxins that act on voltage-gated K+ channels
known toxins specific for chloride and calcium channels (Kv) can be classified into α, β, γ and κ [35, 36]. There
present variable amino acid lengths [26]. The neurotoxins are two main types of structural motifs observed in these
present a highly conserved essential three-dimensional peptide classes: (1) the common motif comprised of one
structure comprising an α-helix and three- or four- or two short α-helices connected to a triple-stranded
stranded anti-parallel β-sheets connected by two to antiparallel β-sheet stabilized by three or four disulfide
four disulfide bonds [18, 27, 28]. bonds, denominated CS αβ and (2) the α-helix-loop-
The scorpion toxins that affect mammalian voltage-gated helix (CS αα) fold consisting of two short α-helices con-
Na+ channels (Nav) are classified as: α-neurotoxins (α- nected by a β-turn; only the kappa toxins adopt this fold
NaScTx) and β-neurotoxins (β-NaScTx). The α-NaScTx [18, 37–40]. The α-neurotoxins (α-KTx) block the pore
interacts with channel receptor site 3 located in the binding to the external vestibule of the channel and
S3–S4 extracellular loop in domain IV and in the S5– block the ionic conductivity by occlusion of the physical
S6 extracellular linker domain I of Nav channels [2, 18]. pore without affecting the kinetics of channel activation
Cordeiro et al. Journal of Venomous Animals and Toxins including Tropical Diseases (2015) 21:24 Page 4 of 14

Table 1 Examples of compounds from Tityus scorpion venoms

Compounds Examples Species Molecular Mass Action Mechanism References
(kDa)
Neurotoxins Ts3, Ts5 Tityus serrulatus ~6.0–7.0 Action on Na+ channels 29–32
TbTx5, Tb3 Tityus bahiensis
Tst3 Tityus stigmurus
Ts1 Tityus serrulatus 6890.9 33–34
Ts6, Ts7 Tityus serrulatus ~6.0–7.0 Action on K+ channels 35–40
Tst26 Tityus stigmurus
Tt28 Tityus trivittatus
TdK1 Tityus discrepans
Hypotensive agent Hypotensin Tityus serrulatus 2.75 Agonist of the B(2) receptor 41
Antimicrobial TsAP1, TsAP2 Tityus serrulatus ~8.4 Unclear 42
peptides
Proteinases Metalloproteinase Tityus serrulatus ~25.0 Lysis of the cell basement membrane 43–46
Serine proteinasesa Tityus serrulatus Tityus – Action on coagulation factors 47
bahiensis
Enzymes Phospholipaseb Tityus serrulatus Tityus – Hydrolysis of membrane 48–49
stigmurus phospholipids
Hyaluronidase Tityus sp. ~50.0 Catalyzes the hydrolysis of hyaluronan 50
from the extracellular matrix
a
Identified in the venom, but not purified
b
Compound found only in the transcriptome

[41]. Ts6 and Ts7 from T. serrulatus, Tst26 from T. The other subclasses of neurotoxins that act on Kv
stigmurus, Tt28 from T. trivittatus and TdK1 from T. channels, such as γ and κ, are less studied. However the
discrepans are examples of α-neurotoxins that act on γ-KTxs neurotoxins were described as mainly targeting
Kv channels [35, 42–45]. hERG channels and were found in scorpions of the
In addition to α-KTxs, the venoms of the Buthidae, genus Centruroides, Mesobuthus and Buthus [18, 36]. The
Caraboctonidae and Scorpioninae families also contain κ-KTxs neurotoxins show an interaction with voltage-
β-neurotoxins (β-KTxs) [35]. According to the identity gated Kv channels similar to α-KTx toxins, presenting the
of the sequences, these toxins may be divided into three lysine and aromatic/hydrophobic residue (functional dyad)
classes. Class 1 containing the toxins TsTX-Kβ-related that interact with the channel [18].
peptides, such as TsTx-Kβ, TtrβKTx, TdiβKTx, TstβKTx, The diversity of toxins that target Kv channels with
Tco 42.14 from T. serrulatus, T. trivittatus, T. discrepans, high affinity and selectivity provides a large number of
T. stigmurus and T. costatus, respectively. The only molecular structures that can be considered for the
peptide characterized to any extent is TsTx-Kβ from T. development of therapeutic drugs for diseases such as
serrulatus, which is a blocker of Kv1.1 channel with cancer and autoimmune diseases, in which there is an
IC50 values of 96 nM [46]. Class 2 consisting of peptides overexpression of these channels [48]. For example,
homologous to BmTXKβ from Buthus martensii which the HERG channels are associated with cell cycle and
showed an inhibition of the transient outward K+ current proliferation of several cancers; therefore, the use of
(Ito) of rabbit atrial myocytes; some examples of class 2 HERG-specific blockers could inhibit the proliferation
peptides are TdiKIK, TtrKIK, TcoKIK and TstKMK [18]. of tumor cells [18].
Class 3 is formed by the Scorpine-like peptides, also The scorpion venoms are composed of other peptides
known as “orphan” peptides. They possess two structural and proteins such as hyaluronidases, antimicrobial peptides,
and functional domains: an N-terminal α-helix (with phospholipases, allergens, hypotensins and also proteinases,
cytolytic and/or anti-microbial activity such as insect such as serine proteinases and metalloproteinases, among
defensins) and a tightly folded C-terminal region with a others. However, some of these molecules were not isolated
CS αβ motif, displaying Kv channel blocking activity. from the scorpion venoms and were only identified in
The scorpine homologs exhibit strong antimicrobial effects the venom gland transcriptome.
as well as cytolytic activity against eukaryotic cells and In addition to the neurotoxic effects induced by toxins
possible antimalarical activity [18, 46, 47]. acting on ion channels, a wide variety of actions of the
Cordeiro et al. Journal of Venomous Animals and Toxins including Tropical Diseases (2015) 21:24 Page 5 of 14

venom components can be observed such as hypotensive One of the major goals of the identification and
and antimicrobial effects induced by TsHpt-I and scor- characterization of animal toxins is the possibility of
pine, respectively. TsHpt-I, isolated from T. serrulatus obtaining new therapeutic drugs. A famous example
venom, acts as an agonist of the B(2) receptor and does about scorpion toxins with biotechnological application
not inhibit angiotensin-converting enzyme [49]. As de- is the chlorotoxin isolated from venom of the Israeli
scribed above, the Tityus venom possesses a peptide scorpion Leiurus quinquestriatus, which was initially devel-
called scorpine which presents an antimicrobial and oped for the diagnosis and treatment of glioma. Further-
antimalarial activity [47]. Recently, Guo et al. [50] identi- more, this toxin was discovered to be capable of labeling
fied two others antimicrobial peptides, TsAP1 and TsAP2, specific cancer cells [63]. Although the biomarker respon-
with broad spectrum antimicrobial and anticancer ac- sible for the binding is still under discussion, it has been
tivities. The antimicrobial peptides are cationic and preliminarily identified as annexin 2A. Recently, the ex-
amphipathic, mostly within 50 amino acid residues, tremely stable iodinated analogue of this toxin—TM601,
were gathered into different groups and their action which presents no immunogenicity and produces no tox-
mechanisms remain unclear [12]. icity in humans—has successfully completed clinical phase
Although the presence of phospholipase was reported II in the treatment of recurrent glioma and was approved
in the transcriptome of T. serrulatus and T. stigmurus, by the Food and Drug Administration (FDA) [63–65].
venoms of T. serrulatus, T. bahiensis and T. stigmurus Thus, given the wealth of components present in scor-
exhibit significant proteolytic but no phospholipase pion venom, it is concluded that the study of these toxins
activity [51–53]. The venom of these scorpions also is not only a potential source of new drugs, but also a
showed metalloproteinase activity; however, this enzyme source of tools in the elucidation of the physiological sys-
was obtained only from T. serrulatus venom [51, 54–56]. tems and envenoming presented by these animals [66].
Furthermore, enzymes that present gelatinolytic activity,
such as serine proteinases, were detected in T. serrulatus Spider venoms
and T. bahiensis venoms, but these toxins have not been Spiders possess four pairs of paws and an external skel-
isolated yet [57]. eton composed of chitin (Fig. 3). The exclusive feature
Hyaluronidase, another important protein present in of these animals is the presence of chelicerae associated
scorpion venom, is considered a “spreading factor” by fa- with the venom gland, except for rare species. The spiders
voring the absorption and spread of venom through the use their venom primarily to paralyze or kill their prey,
tissues of the victim, contributing to local or systemic sometimes for self-defense, which may cause occasional
envenoming [58]. Animals injected with Ts1, the major accidents [67].
toxin from T. serrulatus, and hyaluronidase achieved sig- The World Health Organization (WHO) establishes
nificantly higher serum levels of creatine kinase (CK), that only four spider genera contain species capable of
lactate dehydrogenase (LD) and aspartate aminotransfer- causing medically important accidents in humans: Loxos-
ase (AST) in a shorter time than those injected with only celes, Phoneutria, Latrodectus and Atrax [68]. In Brazil,
Ts1 (without hyaluronidase), confirming the characteris- Loxosceles, Phoneutria and Latrodectus are the most rele-
tic of the “spreading factor” of the hyaluronidase. The vant genera and account for a large number of accidents
animals, which received only hyaluronidase, showed CK, in this country [69].
LD and AST levels similar to those of the control group, Spider venom contains a complex mixture of distinct
indicating no intrinsic toxic effect of hyaluronidase [59]. compounds [70]. The main components are neurotoxins,
The advent of transcriptome analysis of the scorpion proteins, peptides, enzymes, free amino acids and inor-
venom gland allowed the determination of several com- ganic salts. Indeed, many toxins isolated from spider
ponents that had not been purified from the venom of venom have been studied in relation to their role in ion
these animals. Transcriptome of several scorpions has channels [71] (Table 2).
been performed, and among the genus Tityus the transcrip- These cocktails of substances that act by different pharma-
tomes of T. stigmurus, T. discrepans, T. costatus Karsch, T. cological mechanisms have been extensively researched
pachyurus, T. obscurus, T. bahiensis and T. serrulatus have seeking to develop new drugs and biotechnological
been reported [52, 53, 60–62]. These analyses found products [72].
transcripts of novel proteins such as phospholipases, The distinct characteristics of venom from each species
metalloproteinases, allergens, proteinases, antimicrobial determine its effect on humans in the event of an accident.
peptides and anionic peptides. However, the possibility Venom from the genus Loxosceles, or brown spider, has
that those transcripts had undergone microRNA-mediated constituents such as hyaluronidases, metalloproteinases,
degradation during the processing period may explain phospholipases and other enzymes that provide a local ef-
why some toxins were found only in the transcriptome fect with deep lesions, in contrast to the genus Phoneutria,
and not in the venom [53]. whose venom produces neurotoxic activity [73]. The
Cordeiro et al. Journal of Venomous Animals and Toxins including Tropical Diseases (2015) 21:24 Page 6 of 14

Fig. 3 Photo of a spider and schematic representation of a spider’s chelicerae. Chelicerae are associated with venom glands, which are
responsible for the production and storage of venom. The chelicerae are also used to trap and kill the prey

Latrodectus genus, or black widow spider, has neuro- and responsible for most accident cases registered in
toxic venom components that act on presynaptic nerves Brazil. Such accidents occur mostly in the south and
of vertebrates [74]. southeast regions of the country [75, 76].
In this review, we focused only on three genera re- Experimental studies have shown that the venom causes
sponsible for the highest amount of medically important an activation of voltage-dependent sodium channels, and
accidents in Brazil, Loxosceles, Phoneutria and Latrodectus, a blockade of voltage-dependent potassium and calcium
their principal components and respective contributions in channels in muscle fibers and sensory nerve endings in
physio-pharmacological studies. both the motor and autonomic nervous systems. As a con-
sequence, there is a release of neurotransmitters, especially
Biochemical characteristics of the venom from Phoneutria acetylcholine and catecholamines, which explains the fol-
Spiders of the Phoneutria genus are popularly known as lowing symptoms: severe pain at the bite site, sweating,
“armed” due to the attack position they assume in a situ- agitation, salivation and, in severe cases, arrhythmias and
ation of danger. When these spiders face an opponent, they priapism [75, 77, 78].
raise their front legs and lean on the back legs, presenting This venom is a cocktail consisting of peptides, free
aggressive behavior [68]. amino acids, histamine, serotonin and serine proteinases
The venom of this genus causes immediate and intense [79, 80]. Furthermore, the Phoneutria nigriventer venom
local pain radiating in the affected limb, but can progress is largely composed of neurotoxins.
into complications, especially in children and the elderly, The Phoneutria neurotoxins are similar to those from
such as salivation, sudoresis, hypertension, priapism and scorpion venoms. They present different amino acid se-
even death. These spiders are found in banana plants, quences, but are rich in cysteines forming three or four
palm trees and bromeliads. They are habitually nocturnal disulfide bonds, which are responsible for peptide stability.

Table 2 Examples of compounds from Brazilian spider venoms

Compounds Examples Species Molecular Mass Action Mechanism References
(kDa)
Neurotoxins PnTx1,PnTx2, PnTx3 Phoneutria ~6.0–9.0 Act on ion channels 72
nigriventer
PnTx4 Phoneutria 5.17 Inhibit reversible NMDA receptors in insects 73
nigriventer
α-latrotoxin Latrodectus sp. ~130 Influx of Ca2+ on presynaptic nerve endings 74
Enzymes Phospholipase D Loxosceles sp. ~31.0–32.0 Hydrolysis of membrane phospholipids 75
(Sphingomyelinase)
Hyaluronidase Loxosceles sp. – Catalyzes the hydrolysis of hyaluronan from the extracellular 76
matrix
Proteinases Metalloproteinase Loxosceles sp. ~29.0 Lysis of the cell basement membrane 77
Serinoproteinases Loxosceles sp. ~85–95.0 Action on coagulation factors 78
Cordeiro et al. Journal of Venomous Animals and Toxins including Tropical Diseases (2015) 21:24 Page 7 of 14

In this genus, for example, there are three neurotoxins biochemically. Among these are hydrolases, hyaluronidase,
lethal to mice, denominated PnTx1, PnTx2 and PnTx3. lipases, metallo—and serine proteinases, peptidases, colla-
The fraction PnTx4 modifies the neuromuscular re- genases, alkaline phosphatase and phospholipase or sphin-
sponse in insects [75, 79]. gomyelinase D [93–96].
The PnTx2 fraction is composed of nine different pep- The sphingomyelinases are phospholipases D considered
tides, which are mainly responsible for the overall effect the major components of the venom and are primarily
of the venom. Of these nine peptides, the Tx2-5 and responsible for dermonecrotic lesions. Furthermore, these
Tx2-6 are active in smooth muscle relaxation of the cor- enzymes are related to reactions involving components of
pus cavernosum in rats and rabbits, causing erection the complement system, migration of polymorphonuclear
[81–83]. This fact, along with the discovery that some of leukocytes, platelets aggregation and inflammatory re-
these fractions have insecticidal activity, has drawn the sponse [97].
attention of researchers to the study and characterization Although sphingomyelinase D plays a key role in the
of the Phoneutria venom. Loxosceles envenoming and is the major component,
In addition, PnTx4 was able to inhibit glutamate uptake studies have shown that the clinical manifestations are the
by rat synaptosomes. The toxin Tx4(5–5), a polypeptide result of an interaction between several other components
composed of 47 amino acid, displays a potent insecticidal in the venom [98].
activity. This toxin reversibly inhibited the N-methyl-D- Studies of L. gaucho, L. deserta and L. reclusa venom
aspartate (NMDA) subtype receptor [84]. demonstrated the presence of metalloproteinases with
A comparison of the proteomes of P. nigriventer, P. gelatinolytic, caseinolytic and fibrinogenolytic activity.
reidyi and P. keyserlingi revealed a large number of These enzymes appear to be involved with the signs and
neurotoxic peptides that act on ion channels, which symptoms of envenoming. Some of these metallopro-
cause paralysis and death when injected in mice, as well as teinases present astacin-like activity. The astacins are
proteinases and peptides with insecticidal activity and zinc-dependent proteinases with such diverse functions
non-toxic peptides [85]. as hydrolysis, digestion of peptides and degradation of
Spiders contain innumerous peptides with interesting extracellular matrix. These astacin-like metalloproteinases
actions but with a low amount in the venom; for this rea- have been identified in the venom of L. gaucho and L.
son, these components have been synthesized or cloned laeta [93, 95, 99, 100].
and expressed in bacteria or yeast. An example is a recom- In addition, two serine proteinases from the same spe-
binant of PnTx-1 and PnTx3-4 from Phoneutria nigriventer cies of Loxosceles have been reported to hydrolyze gel-
venom. These studies open new perspectives in drug atin [100, 101]. The authors concluded that the activity
development and research [86, 87]. of serine proteinases complements other fibrinogenolytic
proteinases in disseminated intravascular coagulation,
triggered by loxoscelic venom [95, 101]. Furthermore,
Biochemical characteristics of the venom from Loxosceles another enzyme that plays a key role in envenoming is
The different species of the genus Loxosceles are distributed hyaluronidase, which is responsible for the gravitational
globally. They are found in South America, North America, effect on the skin that spreads the venom [73, 95].
Europe, Africa, Oceania and Asia. They are popularly Toxins from Loxosceles venom have been cloned and
known as brown spiders and comprise more than 30 expressed using cDNA. An example of recombinant pro-
species in South America. In Brazil, the highest incidence tein generated by loxoscelic venom is Loxosceles intermedia
of these spiders is in the southern and southeastern regions, recombinant dermonecrotic toxin (LiRecDT), which has
where the L. gaucho, L. laeta and L. intermedia species are properties similar to the L. intermedia venom, with respect
found [73, 88–90]. to inflammatory and dermonecrotic activity, and stimulates
A brown spider bite can cause cutaneous or systemic nephrotoxicity in rats [73]. Furthermore, many sphingo-
(or both in some cases) manifestations in the victims. At myelinases have been cloned from the Loxosceles cDNA
least three actions of the loxoscelic venom are described: glands and expressed to obtain larger amounts of this en-
proteolysis with dermonecrosis at the bite site with a zyme and allow study of the structure and function of these
gravitational lesion; hemolytic action with intravascular toxins [97, 98].
hemolysis, which may lead to acute renal failure, and
coagulant activity with thrombocytopenia, hypofibrino-
genemia, prolongation of clotting time and disseminated Biochemical characteristics of the venom from Latrodectus
intravascular coagulation [91, 92]. genus
Brown spider venom is a mixture of toxins composed Worldwide, more than 40 species of the genus Latrodectus
of proteins and also low-molecular-weight constituents. are found in tropical and subtropical regions. In Brazil,
Numerous toxins have been identified and characterized only three species occur: L. geometricus, L. mactans and L.
Cordeiro et al. Journal of Venomous Animals and Toxins including Tropical Diseases (2015) 21:24 Page 8 of 14

curacaviensis, which inhabit mainly the northeast region three families: Ixodidae, Argasidae and Nuttalliellidae
[102, 103]. However, the presence of another specie, L. [118, 124–126]. There are several genera of ticks, most
mirabilis, was recently described in the southern Brazilian importantly Ixodes, Dermacentor, Boophilus, Rhipicephalus,
state of Rio Grande do Sul [104]. Haemaphysalis, Hyalomma and Amblyomma, which
The bites of these spiders, known as black widows, belong to the family Ixodidae [126].
provoke clinical manifestations that include pain, hyperten- In Brazil, studies have reported the existence of 55
sion, spasms, “facies latrodectismica”, vomiting, abdominal species, divided into six genera of the family Ixodidae
pain and muscle cramping. In severe cases, the patient may (Ixodes, Amblyomma, Haemaphysalis, Anocentor, Rhipice-
present myocardial infarction and compartment syndrome phalus and Boophilus) and four genera of the Argasidae
[102, 105]. family (Argas, Ornithodoros, Antricola and Otobius). The
The Latrodecuts venom contains a cocktail of substances, Ixodidae family includes the most of the species of medical
but its major component is α-latrotoxin (α-LTX), a neuro- and veterinary importance in Brazil, where the genus
toxin that acts selectively on presynaptic nerve endings and Amblyomma (the largest genus containing 33 species)
provokes a discharge of neurotransmitters. This toxin is a is the most important in the medical field. The species
protein with high molecular mass (about 130 kDa of ma- Amblyomma cajennense, A. aureolatum and A. cooperi
ture toxin), but shows no enzymatic activity [74, 106–110]. stand out in relation to the transmission of spotted
The effects of the LTX seem to be related to the for- fever [127, 128].
mation of pores in the membrane. LTX binds to specific Morphologically, ticks present two fused parts, namely
receptors (named neurexin and latrophilin) which can the capitulum (or gnathosoma) that contains the head
facilitate the insertion of this toxin and subsequent in- and mouthparts, and the idiosoma that contains the legs,
flux of Ca2+ [106, 111, 112]. digestive tract and reproductive organs (Fig. 4). The ca-
LTXs have targeted insects (latroinsectotoxins), crusta- pitulum consists of three specialized structures: palpus,
ceans (latrocrustatoxin) and mammals. Many of these chelicerae and a hypostome. Nymph and adult ticks have
latrotoxins have been cloned and studied in relation to eight legs whereas larval ticks possess six [118, 124, 129].
their structure, maturation and activity. Moreover, these Several diseases can be transmitted during feeding by
toxins can help to elucidate the mechanisms of neuro- ticks, which are obligate hematophagous organisms. Der-
transmitter release and to identify neuronal cell-surface mal and epidermal damage (rupture of local blood vessels)
receptors [113]. are consequences of the insertion of the tick hypostome
[125–127]. In contrast to the toxins of other arthropods
such as scorpions and spiders, which utilize their toxins
Ticks for protection as well as predation, the advantages of the
The known tickborne diseases are of great interest in the tick toxins are still unclear and require additional research
field of public health. Ticks are rarely considered venomous [130, 131]. We will discuss below the main compounds
but some studies provide evidence to the contrary found in saliva from Brazilian families of ticks.
[5, 114–116]. Ticks, as vectors of disease transmission to
humans, rank just behind mosquitoes as the most import- Biochemical characteristics of tick saliva
ant arthropod transmitters of pathogens to several animal Studies performed to evaluate the pharmacological com-
species [117]. Although these diseases have focal features plexity presented by hematophagous arthropods have
on some regions, they have been recognized worldwide. shown that their saliva contains at least one anticlotting,
Virus and bacteria are the main causes of the diseases one vasodilatory and one anti-platelet substance [132].
transmitted by ticks. Among the virus-associated Among tick saliva components are descriptions of enzymes,
diseases, we can cite encephalitis, Crimean-Congo enzyme inhibitors, host protein homologues, amine-
hemorrhagic fever, Omsk hemorrhagic fever, Colorado binding lipocalins, immunoglobulin-binding proteins,
tick fever, Powassan encephalitis, Langat encephalitis and receptor agonist/antagonist, calcium-binding components,
louping ill encephalitis. Some tickborne diseases associ- cement cytokine components, cytokine expression modu-
ated with bacteria have already been described including lators, non-proteinaceous bioactive components and other
tularemia, ehrlichiosis (monocytic and granulocity), rick- components related to cardiotoxic and neurotoxic factors
ettsiosis (spotted fever), Lyme borreliosis (Lyme disease) [118, 119, 127, 130, 132, 133].
as well an infection caused by a protozoan, babesiosis The Amblyomma cajennense is the most studied species
[118–123]. in Brazil. After constructing a cDNA library on this tick, a
Ticks are cosmopolitan and associated with numerous dis- serine protease Kunitz-type inhibitor was designed. This
eases besides being the most important group of ectopara- new inhibitor known as Amblyomin-X was able to decrease
sites of wild animals [118, 124]. Today, approximately 899 the number of metastatic events and the tumor mass in a
tick species have been described and distributed among B16F10 murine melanoma model by apoptosis induction
Cordeiro et al. Journal of Venomous Animals and Toxins including Tropical Diseases (2015) 21:24 Page 9 of 14

Fig. 4 Photo of a tick and schematic representation of the capitulum. Dorsal and ventral morphology of the mouthpart of Ixodidae family ticks.
On the dorsum it is possible to observe the chelicerae while the venter displays the hypostome. The palpus is observable on both sides (dorsum
and venter). The hypostome is responsible for the dermal and epidermal damage (rupture of local blood vessels) during the tick’s feeding

[134–136]. Moreover, the Amblyomin-X was able to inhibit neurotoxins such as HT-1 (holocyclotoxins) in the
the factor Xa from coagulation cascade [136]. Although this Ixodes holocyclus tick saliva and another still unnamed
species is the most studied in Brazil, most studies have one in the Rhipicephalus evertsi evertsi tick saliva
focused on characterization and therapeutic application [127, 146, 147].
of Amblyomin-X [134–136]. The gene coding of the HT-1 neurotoxin in the saliva
Saliva-enzyme inhibitors have great biotechnological of the tick I. holocyclus showed high homology with the
potential in the medical field. Ornithodorin (Ornitho- gene coding scorpion neurotoxin [114, 146]. The study
doros moubata) and savignin (Ornithodoros savignyi) are of this toxin may help elucidate the potentially fatal tick
examples of potent thrombin inhibitors from tick saliva paralysis caused by this arthropod [127, 146–157].
[137, 138]. A novel tissue factor pathway inhibitor called The presence of the phospholipase A2 (PLA2) was ob-
ixolaris was found through the sialotranscriptome ana- served in saliva from Amblyomma americanum. This en-
lysis of I. scapularis [139, 140]. Among the inhibitors of zyme is secreted in the tick-host interface, and probably
factor Xa, Salp14 is the main prototype identified in I. plays an important role during prolonged tick feeding. The
scapularis saliva, whereas tick anticoagulant peptide (TAP) PLA2 does not contribute to the anticoagulant activities
is the main inhibitor of factor Xa from Ornithodoros but is associated with hemolytic activity observed during
moubata [141–144]. Variegin isolated from Amblyomma feeding [158, 159].
variegatum saliva is one of the smallest thrombin inhib- Some lectins were characterized in the ticks O. mou-
itors (3.6 kDa) identified in nature. This inhibitor binds bata (Dorin M and OMFREP) and I. ricinus (ixoderin
to thrombin with strong affinity and is considered an A and ixoderin B). Lectins play roles in the innate im-
excellent model for the development of new inhibitors munity of ticks whereas that of R. microplus induces
of this class [145]. immunosuppression in mice [5, 160–162].
In contrast to the scorpions, few neurotoxins were An antimicrobial protein was identified in the hemolymph
found in tick saliva to date. Some studies described of the tick Amblyomma hebraeum and denominated
Cordeiro et al. Journal of Venomous Animals and Toxins including Tropical Diseases (2015) 21:24 Page 10 of 14

hebraein (11 kDa). Native hebraein and its recombinant showing antimicrobial activity against all standard
form, named hebraeinsin, revealed antimicrobial strains [168].
activities against the gram-positive and gram-negative bac- Defensins are small proteins present in vertebrates, in-
teria (S. aureus and E. coli, respectively) and the fungus vertebrates and plants and are responsible for their
Candida glabrata [163]. In another study, two non- defense against several microorganisms. Two isoforms of
cationic defensin-like antimicrobial peptides, designated the defensin gene, denominated def1 and def2, were
Amblyomma defensin peptide 1 and Amblyomma defen- found in saliva of Ixodes ricinus ticks; synthetic peptides
sin peptide 2, were found in the Amblyomma hebraeum from these defensins were tested against bacteria and
tick saliva [164]. The Amblyomma defensin peptide 2 yeast [169]. These defensins showed an antimicrobial
showed antimicrobial activity against E. coli and S. aureus. activity against gram-positive bacteria, but were not ef-
Ixosin, another antimicrobial peptide, was isolated from fective against gram-negative ones or yeast [169]. Struc-
salivary glands of the tick Ixodes sinensis. This peptide has turally, these defensins contain six cysteine residues
23 amino acids (without cysteine) and showed antimicro- and present as their main action mechanism cell mem-
bial activity against E. coli, S. aureus and C. albicans [165]. brane lysis by a formation of channels [169]. With the
Ixosin-B was purified and cloned from salivary glands of increasing number of microorganisms resistant to con-
the Ixodes sinensis and showed antimicrobial activity ventional antibiotics, the saliva of ticks is becoming an
against E. coli, S. aureus and C. albicans [166]. ISAMP, an important source for the discovery of new compounds
antimicrobial peptide from Ixodes scapularis saliva, has a to treat several diseases.
molecular weight of 5.3 kDa and exhibited antimicrobial
activity against gram-negative and gram-positive bacteria.
Additionally, it showed insignificant hemolytic action Conclusions
on rabbit red blood cells, suggesting that it is a safe In this review we have highlighted the main biologically
antimicrobial peptide for possible use on mammals [167]. active components present in scorpion and spider venoms,
Table 3 summarizes the major components found in the as well as tick saliva, which are of great importance in
tick saliva. the medical field in Brazil. We have also shown that
After the identification of molecules with important the study of arachnid venoms and saliva provides numerous
pharmacological actions from natural sources, another compounds with great biotechnological potential. The bio-
possible alternative to obtain peptides is chemical chemical characterization of these compounds, combined
synthesis. Zheng et al. [168] synthetized a defensin- with the advent of molecular biology techniques, enables
like antimicrobial peptide obtained from a cDNA li- the development of new biotechnological products with
brary of the male accessory glands of Haemaphysalis relevant applications. Additionally, this study allows the un-
longicornis. This peptide, based on the predicted mature derstanding of the physiological processes involved in the
portion of HlMS-defensin, was tested against a variety envenomings and diseases transmitted by ticks, thereby fa-
of gram-positive and gram-negative bacteria and fungi, cilitating the obtainment of a more effective therapy.

Table 3 Examples of compounds from tick saliva

Compounds Examples Species Molecular Mass Mechanism of Action References
(kDa)a
Enzyme Amblyomin-Xb Amblyomma 15.0 Factor Xa Inhibition/induction of apoptosis in 134–136
Inhibitors cajennense tumor cells
Savignin Ornithodoros savignyi 14.1 Thrombin inhibitor 137–138
Ixolaris Ixodes scapularis 18.4 Tissue factor pathway inhibitor 139–140
Variegin Amblyomma 3.6 Thrombin inhibitor 145
variegatum
Neurotoxin HT-1 Ixodes holocyclus 7.8 Unclear 114, 146–
(Holocyclotoxins) 148
Enzyme Phospholipase A2 Amblyomma 55.7 ± 1.3 Hydrolysis of membrane phospholipids 158–159
americanum
Proteins Hebraein Amblyomma 11.0 Unclear 163
hebraeum
Ixosin Ixodes sinensis 8.8 Unclear 165
ISAMP Ixodes scapularis 5.3 Unclear 167
a
Data obtained from references and uniprot.org
b
Compound found only in the transcriptome
Cordeiro et al. Journal of Venomous Animals and Toxins including Tropical Diseases (2015) 21:24 Page 11 of 14

Abbreviations 19. Possani LD, Becerril B, Delepierre M, Tytgat J. Scorpion toxins specific for
α-NaScTx: α-neurotoxins with action on Na+ channels; α-KTx: α-neurotoxins Na + −channels. Eur J Biochem. 1999;264(2):287–300.
with action on K+ channels; α-LTX: α-latrotoxin; β-NaScTx: β-neurotoxins with 20. Watt DD, Simard JM. Neurotoxic proteins in scorpion venom. J Toxicol Toxin
action on Na+ channels; β-KTxs: β-neurotoxins with action on K+ channels; Rev. 1984;3(2–3):181–221.
γ-KTxs: γ-neurotoxins with action on K+ channels; κ-KTxs: κ-neurotoxins with 21. Pucca MB, Amorim FG, Cerni FA, Bordon KDCF, Cardoso IA, Anjolette FAP,
action on K+ channels; AST: Aspartate aminotransferase; AVIT: Alanine-valine- et al. Influence of post-starvation extraction time and prey-specific diet in
isoleucine-threonine; CAP: Catabolite activator protein; CK: Creatine kinase; Tityus serrulatus scorpion venom composition and hyaluronidase activity.
Kv: Voltage-gated K+ channels; LD: Lactate dehydrogenase; Nav: Voltage- Toxicon. 2014;90:326–36.
gated Na+ channels; PLA2: Phospholipase A2. 22. Oliveira FN, Mortari MR, Carneiro FP, Guerrero-Vargas JA, Santos DM,
Pimenta A, et al. Another record of significant regional variation in toxicity
Competing interests of Tityus serrulatus venom in Brazil: a step towards understanding the
The authors declare that there are no competing interests. possible role of sodium channel modulators. Toxicon. 2013;73:33–46.
23. Rodríguez-Ravelo R, Coronas FI, Zamudio FZ, González-Morales L, López GE,
Authors’ contributions Urquiola AR, et al. The Cuban scorpion Rhopalurus junceus (Scorpiones,
All the authors contributed equally to this work. However, the topics were Buthidae): component variations in venom samples collected in different
divided: FGA (scorpion venom), FAC (spider venom) and FAPA (tick saliva). geographical areas. J Venom Anim Toxins incl Trop Dis. 2013;19:13.
ECA is the corresponding author and designer of the research. All authors 24. Kalapothakis E, Chávez-Olórtegui C. Venom variability among several Tityus
read and approved the final manuscript. serrulatus specimens. Toxicon. 1997;35(10):1523–9.
25. Tan PT, Veeramani A, Srinivasan KN, Ranganathan S, Brusic V. SCORPION2:
Acknowledgments a database for structure-function analysis of scorpion toxins. Toxicon.
The authors are indebted to the National Council for Scientific and 2006;47(3):356–63.
Technological Development (CNPq), the State of São Paulo Research 26. Possani LD, Merino E, Corona M, Bolivar F, Becerril B. Peptides and genes coding
Foundation (FAPESP – scholarship to FGA, n. 2011/12317-3) and the for scorpion toxins that affect ion-channels. Biochimie. 2000;82(9–10):861–8.
Coordination for the Improvement of Higher Education Personnel 27. Housset D, Habersetzer-Rochat C, Astier JP, Fontecilla-Camps JC. Crystal
(CAPES—scholarship to FAC and FAPA) and the Support Nucleus for structure of toxin II from the scorpion Androctonus australis Hector refined
Research on Animal Toxins (NAP-TOXAN-USP, grant n. 12–125432.1.3) for at 1.3 A resolution. J Mol Biol. 1994;238(1):88–103.
financial support. Thanks are also due to the Center for the Study of Venoms 28. Oren DA, Froy O, Amit E, Kleinberger-Doron N, Gurevitz M, Shaanan B. An
and Venomous Animals (CEVAP) of UNESP for enabling the publication of excitatory scorpion toxin with a distinctive feature: an additional α helix at
this special collection (CNPq process 469660/2014–7). the C terminus and its implications for interaction with insect sodium
channels. Structure. 1998;6(9):1095–103.
Received: 5 December 2014 Accepted: 21 July 2015 29. Possani LD, Martin BM, Fletcher MD, Fletcher Jr PL. Discharge effect on
pancreatic exocrine secretion produced by toxins purified from Tityus
serrulatus scorpion venom. J Biol Chem. 1991;266(5):3178–85.
References 30. Kalapothakis E, Jardim S, Magalhães AC, Mendes TM, de Marco L, Afonso LC,
1. World Health Organization. Neglected tropical diseases: the 17 neglected et al. Screening of expression libraries using ELISA: identification of
tropical diseases. http://www.who.int/neglected_diseases/diseases/ immunogenic proteins from Tityus bahiensis and Tityus serrulatus venom.
summary/en/ Toxicon. 2001;39(5):679–85.
2. Marcussi S, Arantes EC, Soares AM. Escorpiões: biologia, envenenamento e 31. Batista CV, Román-González SA, Salas-Castillo SP, Zamudio FZ, Gómez-Lagunas
mecanismos de ação de suas toxinas. Ribeirão Preto: Fundação de F, Possani LD. Proteomic analysis of the venom from the scorpion Tityus
Pesquisas Científicas (FUNPEC); 2011. stigmurus: biochemical and physiological comparison with other Tityus species.
3. Buchel W. Acúleos que matam. São Paulo: Revistas dos Tribunais; 1979. p. 153. Comp Biochem Physiol C Toxicol Pharmacol. 2007;146(1–2):147–57.
4. Likes K, Banner Jr W, Chavez M. Centruroides exilicauda envenomation in 32. Teixeira CE, de Oliveira JF, Baracat JS, Priviero FB, Okuyama CE, Rodrigues
Arizona. West J Med. 1984;141(5):634–7. Netto Jr N, et al. Nitric oxide release from human corpus cavernosum
5. Cabezas-Cruz A, Valdés JJ. Are ticks venomous animals? Front Zool. 2014;11:47. induced by a purified scorpion toxin. Urology. 2004;63(1):184–9.
6. Regier JC, Shultz JW, Zwick A, Hussey A, Ball B, Werzer R, et al. Arthropod 33. Becerril B, Marangoni S, Possani LD. Toxins and genes isolated from
relationships revealed by phylogenomic analysis of nuclear protein-coding scorpions of the genus Tityus. Toxicon. 1997;35(6):821–35.
sequences. Nature. 2010;463:1079–83. 34. Zoccal KF, Bitencourt Cda S, Secatto A, Sorgi CA, Bordon Kde C, Sampaio SV,
7. Bawaskar HS, Bawaskar PH. Scorpion sting: update. J Assoc Phys India. et al. Tityus serrulatus venom and toxins Ts1, Ts2 and Ts6 induce macrophage
2012;60:46–55. activation and production of immune mediators. Toxicon. 2011;57(7–8):1101–8.
8. Chippaux JP. Emerging options for the management of scorpion stings. 35. Tytgat J, Chandy KG, Garcia ML, Gutman GA, Martin-Eauclaire MF, van der Walt JJ,
Drug Des Devel Ther. 2012;6:165–73. et al. A uniform nomenclature for short-chain peptides isolated from scorpion
9. Portal Saúde: Acidentes por Escorpiões. http://portalsaude.saude.gov.br (2012). venoms: α - KTx molecular subfamilies. Trends Pharmacol Sci. 1999;20(11):444–7.
10. Warrell DA. Venomous bites, stings, and poisoning. Infect Dis Clin North Am. 36. Corona M, Gurrola GB, Merino E, Cassulini RR, Valdez-Cruz NA, García FIV, et al. A
2012;26(2):207–23. large number of novel Ergtoxin-like genes and ERG K + −channels blocking
11. Cologna CT, Marcussi S, Giglio JR, Soares AM, Arantes EC. Tityus serrulatus peptides from scorpions of the genus Centruroides. FEBS Lett. 2002;532(1–2):121–6.
scorpion venom and toxins: an overview. Protein Pept Lett. 2009;16(8):920–32. 37. Rodríguez de la Vega RC, Possani LD. Current views on scorpion toxins
12. Hmed BN, Serria HT, Mounir ZK. Scorpion peptides: potential use for new specific for K + −channels. Toxicon. 2004;43(8):865–75.
drug development. J Toxicol. 2013;2013:958797. doi:10.1155/2013/958797. 38. Mouhat S, Jouirou B, Mosbah A, de Waard M, Sabatier J. Diversity of folds in
13. Norwegian University of Science & Technology : The scorpion files. animal toxins acting on ion channels. Biochem J. 2004;378(Pt 3):717–26.
http://www.ntnu.no/ub/scorpion-files/. 39. Chagot B, Pimentel C, Dai L, Pil J, Tytgat J, Nakajima T, et al. An unusual fold
14. Bosmans F, Tytgat J. Voltage-gated sodium channel modulation by scorpion for potassium channel blockers: NMR structure of three toxins from the
alpha-toxins. Toxicon. 2007;49(2):142–58. scorpion Opisthacanthus madagascariensis. Biochem J. 2005;388(Pt 1):263–71.
15. Balozet L. Scorpionism in the Old World. In: Bucherl W, Buckley EE, editors. 40. Saucedo AL, Flores-Solis D, de la Vega RC R, Ramírez-Cordero B, Hernández-
Venomous animals and their venoms. New York: Academic Press; 1971. p. 349–71. López R, Cano-Sánchez P, et al. New tricks of an old pattern structural versatility
16. Reckziegel GC, Pinto VL. Scorpionism in Brazil in the years 2000 to 2012. of scorpion toxins with common cysteine spacing. J Biol Chem. 2012;287:12321–30.
J Venom Anim Toxins incl Trop Dis. 2014;20:46. 41. Giangiacomo KM, Garcia ML, McManus OB. Mechanism of iberiotoxin block
17. Dorce ALC, Dorce VA, Nencioni ALA. Mild reproductive effects of the Tityus of the large-conductance calcium-activated potassium channel from bovine
bahiensis scorpion venom in rats. J Venom Anim Toxins incl Trop Dis. 2014;20:4. aortic smooth muscle. Biochemistry. 1992;31:6719–27.
18. Quintero-Hernández V, Jiménez-Vargas JM, Gurrola GB, Valdivia HH, Possani 42. Blaustein MP, Rogowski RS, Schneider MJ, Krueger BK. Polypeptide toxins
LD. Scorpion venom components that affect ion-channels function. Toxicon. from the venoms of Old World and New World scorpions preferentially
2013;76:328–42. block different potassium channels. Mol Pharmacol. 1991;40(6):932–42.
Cordeiro et al. Journal of Venomous Animals and Toxins including Tropical Diseases (2015) 21:24 Page 12 of 14

43. Papp F, Batista CV, Varga Z, Herceg M, Román-González SA, Gaspar R, et al. 66. Watkins JB. Properties and toxicities of animal venoms. In: Klaassen CD,
Tst26, a novel peptide blocker of Kv1.2 and Kv1.3 channels from the venom editor. Casarett & Doull’s toxicology: the basic science of poisons. 7th ed.
of Tityus stigmurus. Toxicon. 2009;54(4):379–89. New York: McGraw-Hill; 2008. p. 1083–102.
44. Abdel-Mottaleb Y, Coronas FV, de Roodt AR, Possani LD, Tytgat JA. A novel 67. Minton SA Jr. Venom diseases. 1 st ed. Springfield: Charles C. Thomas
toxin from the venom of the scorpion Tityus trivittatus, is the first member Publisher LTD; 1974.
of a new alpha-KTx subfamily. FEBS Lett. 2006;580(2):592–6. 68. Lucas SM. Aranhas de interesse médico no Brasil. In: Cardoso JLC, Haddad
45. D’Suze G, Zamudio F, Gómez-Lagunas F, Possani LD. A novel K+ channel Junior V, França FS, editors. Animais peçonhentos no Brasil: biologia, clínica
blocking toxin from Tityus discrepans scorpion venom. FEBS Lett. 1999;456(1):146–8. e terapêutica dos acidentes. São Paulo: Sarvier; 2009. p. 157–65.
46. Diego-García E, Abdel-Mottaleb Y, Schwartz EF, Rodríguez De L, Vega RC, 69. Cristiano MP, Cardoso DC, Raymundo MS. Contextual analysis and epidemiology
Tytgat J, et al. Cytolytic and K+ channel blocking activities of beta-KTx and of spider bite in southern Santa Catarina state, Brazil. Trans R Soc Trop Med Hyg.
scorpine-like peptides purified from scorpion venoms. Cell Mol Life Sci. 2009;103:943–8.
2008;65(1):187–200. 70. Jackson H, Parks TN. Spider toxins: recent applications in neurobiology. Ann
47. Diego-García E, Schwartz EF, D’Suze G, González SA, Batista CV, García BI, et Rev Neurosci. 1989;12:405–14.
al. Wide phylogenetic distribution of scorpine and long-chain beta-KTx-like 71. Rash LD, Hodgson WC. Pharmacology and biochemistry of spider venoms.
peptides in scorpion venoms: identification of “orphan” components. Peptides. Toxicon. 2002;40(3):225–54.
2007;28(1):31–7. 72. Nicholson GM, Graudins A, Wilson HI, Little M, Broady KW. Arachnid toxinology in
48. Wulff H, Castle NA, Pardo LA. Voltage-gated potassium channels as therapeutic Australia: from clinical toxicology to potential applications. Toxicon. 2006;48(7):872–98.
drug targets. Nat Rev Drug Discov. 2009;8(12):982–1001. 73. Senff-Ribeiro A, Henrique Da Silva P, Chaim OM, Gremski LH, Paludo KS,
49. Verano-Braga T, Figueiredo-Rezende F, Melo MN, Lautner RQ, Gomes ER, Bertoni Da Silveira R. Biotechnological applications of brown spider
Mata-Machado LT, et al. Structure-function studies of Tityus serrulatus (Loxosceles genus) venom toxins. Biotechnol Adv. 2008;26(3):210–8.
Hypotensin-I (TsHpt-I): A new agonist of B(2) kinin receptor. Toxicon. 74. Kiyatkin NI, Dulubova IE, Chekhovskaya IA, Grishin EV. Cloning and structure
2010;56(7):1162–71. of cDNA encoding α-latrotoxin from black widow spider venom. FEBS Lett.
50. Guo X, Ma C, Du Q, Wei R, Wang L, Zhou M, et al. Two peptides, TsAP-1 and 1990;270(1–2):127–31.
TsAP-2, from the venom of the Brazilian yellow scorpion, Tityus serrulatus: 75. Antunes E, Málaque CMS. Mecanismo de ação do veneno de Phoneutria e
evaluation of their antimicrobial and anticancer activities. Biochimie. aspectos clínicos do foneutrismo. In: Cardoso JLC, Haddad Junior V, França
2013;95(9):1784–94. FS, editors. Animais peçonhentos no Brasil: biologia, clínica e terapêutica
51. Venancio EJ, Portaro FC, Kuniuoshi AK, Carvalho DC, Pidde-Queiroz G, dos acidentes. São Paulo: Sarvier; 2009. p. 166–75.
Tambourgi DV. Enzymatic properties of venoms from Brazilian scorpions of 76. Lucas SM. Spiders in Brazil. Toxicon. 1988;26:759–72.
Tityus genus and the neutralisation potencial of therapeutical antivenoms. 77. de Lima ME, Borges MH, Verano-Braga T, Torres FS, Montandon GG, Cardoso
Toxicon. 2013;69:180–90. FL, et al. Some arachnidan peptides with potential medical application.
52. Almeida DD, Scortecci KC, Kobashi LS, Agnez-Lima LF, Medeiros SR, Silva-Junior J Venom Anim Toxins incl Trop Dis. 2010;16(1):8–33.
AA, et al. Profiling the resting venom gland of the scorpion Tityus stigmurus 78. Teixeira CE, Corrado AP, de Nucci G, Antunes E. Role of Ca2+ in vascular
through a transcriptomic survey. BMC Genomics. 2012;13:362. smooth muscle contractions induced by Phoneutria nigriventer spider
53. Alvarenga ER, Mendes TM, Magalhães BF, Siqueira FF, Dantas AE, Barroca venom. Toxicon. 2004;43(1):61–8.
TM, et al. Transcriptome analysis of the Tityus serrulatus scorpion venom 79. Rezende Júnior L, Cordeiro MN, Oliveira EB, Diniz CR. Isolation of neurotoxic
gland. Open J Genetics. 2012;2(4):210–20. peptides from the venom of the “armed” spider Phoneutria nigriventer.
54. Flecther Jr PL, Fletcher MD, Weninger K, Anderson TE, Martin BM. Vesicle- Toxicon. 1991;29(10):1225–33.
associated membrane protein (VAMP) cleavage by a new metalloprotease 80. Nunes KP, Costa-Gonçalves A, Lanza LF, Cortes SF, Cordeiro MN, Richardson
from the Brazilian scorpion Tityus serrulatus. J Biol Chem. 2009;285(10):7405–16. M, et al. Tx2-6 toxin of the Phoneutria nigriventer spider potentiates rat
55. Ortiz E, Rendón-Anaya M, Rego SC, Schwartz EF, Possani LD. Antarease-like erectile function. Toxicon. 2008;51(7):1197–206.
Zn-metalloproteases are ubiquitous in the venom of different scorpion 81. Andrade E, Villanova F, Borra P, Leite K, Troncone L, Cortez I, et al. Penile
genera. Biochim Biophys Acta. 2013;1840(6):1738–46. erection induced in vivo by a purified toxin from the Brazilian spider
56. Carmo AO, Oliveira-Mendes BB, Horta CC, Magalhães BF, Dantas AE, Chaves Phoneutria nigriventer. BJU Int. 2008;102(7):835–7.
LM, et al. Molecular and functional characterization of metalloserrulases, new 82. Leite KR, Andrade E, Ramos AT, Magnoli FC, Srougi M, Troncone LR.
metalloproteases from the Tityus serrulatus venom gland. Toxicon. 2014;90:45–55. Phoneutria nigriventer spider toxin Tx2-6 causes priapism and death: a
57. Almeida FM, Pimenta AM, de Figueiredo SG, Santoro MM, Martin-Eauclaire histopathological investigation in mice. Toxicon. 2012;60(5):797–801.
MF, Diniz CR, et al. Enzymes with gelatinolytic activity can be found in Tityus 83. Jung AR, Choi YS, Piao S, Park YH, Shrestha KR, Jeon SH, et al. The effect of
bahiensis and Tityus serrulatus venoms. Toxicon. 2002;40(7):1041–5. PnTx2-6 protein from Phoneutria nigriventer spider toxin on improvement of
58. Pukrittayakamee S, Warell DA, Desakorn V, McMichael AJ, White NJ, Bunnag erectile dysfunction in a rat model of cavernous nerve injury. Urology.
D. The hyaluronidase activities of some southeast Asian snake venoms. 2014;84(3):730.
Toxicon. 1988;26(7):629–37. 84. De Figueiredo SG, de Lima ME, Nascimento Cordeiro M, Diniz CR, Patten D,
59. Pessini AC, Takao TT, Cavalheiro EC, Vichnewski W, Sampaio SV, Giglio JR, et Halliwell RF, et al. Purification and amino acid sequence of a highly insecticidal
al. A hyaluronidase from Tityus serrulatus scorpion venom: isolation, toxin from the venom of the brazilian spider Phoneutria nigriventer which inhibits
characterization and inhibition by flavonoids. Toxicon. 2001;39(10):1495–504. NMDA-evoked currents in rat hippocampal neurones. Toxicon. 2001;39(2–3):309–17.
60. D’Suze G, Schwartz EF, García-Gómez BI, Sevcik C, Possani LD. Molecular 85. Richardson M, Pimenta AM, Bemquerer MP, Santoro MM, Beirão PSL, Lima
cloning and nucleotide sequence analysis of genes from a cDNA library of ME, et al. Comparison of the partial proteomes of the venoms of Brazilian
the scorpion Tityus discrepans. Biochimie. 2009;91(8):1010–9. spiders of the genus Phoneutria. Comp Biochem Physiol C Toxicol
61. Diego-García E, Batista CV, García-Gómez BI, Lucas S, Candido DM, Pharmacol. 2006;142(3–4):173–87.
Gómez-Lagunas F, et al. The Brazilian scorpion Tityus costatus Karsch: 86. Silva AO, Peigneur S, Diniz MR, Tytgat J, Beirão PS. Inhibitory effect of the
genes, peptides and function. Toxicon. 2005;45(3):273–83. recombinant Phoneutria nigriventer Tx1 toxin on voltage-gated sodium
62. Guerrero-Vargas JA, Mourão CB, Quintero-Hernández V, Possani LD, Schwartz channels. Biochimie. 2012;94(12):2756–63.
EF. Identification and phylogenetic analysis of Tityus pachyurus and Tityus obscurus 87. Souza IA, Cino EA, Choy WY, Cordeiro MN, Richardson M, Chavez-Olortegui
novel putative Na + −channel scorpion toxins. PLoS One. 2012;7(2):e30478. C, et al. Expression of a recombinant Phoneutria toxin active in calcium channels.
63. Sabatier JM, Waard M. Animal toxins in the world of modern biotechnology. Toxicon. 2012;60(5):907–18.
In: Kastin AJ, editor. Handbook of biologically active peptides. United States: 88. Barbaro KC, Cardoso JLC. Mecanismo de ação do veneno de Loxosceles e
Elsevier; 2013. p. 407–15. aspectos clínicos do Loxoscelismo. In: Cardoso JLC, França FS, Fan FW, Malaque
64. Mamelak AN, Rosenfeld S, Bucholz R, Raubitschek A, Nabors LB, Fiveash JB, CM, Haddad Junior V, editors. Animais peçonhentos no Brasil: biologia, clínica e
et al. Phase I single-dose study of intracavitary-administered iodine-131-TM-601 terapêutica dos acidentes. São Paulo: Sarvier; 2009. p. 160–74.
in adults with recurrent high-grade glioma. J Clin Oncol. 2006;24(22):3644–50. 89. Machado LHA, Antunes MIPP, Mazini AM, Sakate M, Torres-Neto R, Fabris VE,
65. Soroceanu L, Gillespie Y, Khazaeli MB, Sontheimer H. Use of chlorotoxin for et al. Necrotic skin lesion in a dog attributed to Loxosceles (brown spider)
targeting of primary brain tumors. Cancer Res. 1998;58(21):4871–9. bite: a case report. J Venom Anim Toxins incl Trop Dis. 2009;15(3):572–81.
Cordeiro et al. Journal of Venomous Animals and Toxins including Tropical Diseases (2015) 21:24 Page 13 of 14

90. Ramada JS, Becker-Finco A, Minozzo JC, Felicori LF, de Avila RA M, Molina F, 115. Low DH, Sunagar K, Undheim EA, Ali SA, Alagon AC, Ruder T, et al. Dracula’s
et al. Synthetic peptides for in vitro evaluation of the neutralizing potency children: molecular evolution of vampire bat venom. J Proteomics.
of Loxosceles antivenoms. Toxicon. 2013;73:47–55. 2013;89:95–111.
91. Cardoso JLC. Acidentes por Loxosceles (Loxoscelismo). In: Schvartsman S, editor. 116. Francischetti IM, Assumpção TC, Ma D, Li Y, Vicente EC, Uieda W, et al. The
Plantas venenosas e animais peçonhentos. São Paulo: Sarvier; 1992. p. 201–4. “Vampirome”: transcriptome and proteome analysis of the principal and
92. Machado LF, Laugesen S, Botelho ED, Ricart CA, Fontes W, Barbaro KC, et al. accessory submaxillary glands of the vampire bat Desmodus rotundus, a
Proteome analysis of brown spider venom: identification of loxnecrogin vector of human rabies. J Proteomics. 2013;82:288–319.
isoforms in Loxosceles gaucho venom. Proteomics. 2005;5(8):2167–76. 117. Parola P, Raoult D. Ticks and tickborne bacterial diseases in humans: an
93. Feitosa L, Gremski W, Veiga SS, Elias MC, Graner E, Mangili OC, et al. emerging infectious threat. Clin Infect Dis. 2012;32(6):271–8.
Detection and characterization of metalloproteinases with gelatinolytic, 118. Anderson JF, Magnarelli LA. Biology of ticks. Infect Dis Clin North Am.
fibronectinolytic and fibrinogenolytic activities in brown spider (Loxosceles 2008;22(2):195–215.
intermedia) venom. Toxicon. 1998;36:1039–51. 119. Organização Pan-Americana da Saúde. Consulta de especialistas OPAS/OMS
94. Hogan CJ, Barbaro KC, Winkel K. Loxoscelism: old obstacles, new directions. sobre Rickettioses nas Américas. Relatório Final. Ouro Preto: Organização
Ann Emerg Med. 2004;44(6):608–24. Pan-americana de saúde; 2004.
95. Barbaro KC, Sousa MV, Morhy L, Eickstedt VR, Mota I. Compared chemical 120. Estrada-Peña A, Hubálek Z, Rudolf I. Tick-transmitted viruses and climate
properties of dermonecrotic and lethal toxins from spiders of the genus change. In: Singh SK, editor. Viral Infections and Global Change. Hoboken:
Loxosceles(Araneae). J Protein Chem. 1996;15(4):337–43. John Wiley & Sons, Inc; 2013. p. 573–94.
96. da Silva PH, da Silveira RB, Appel MH, Mangili OC, Gremski W, Veiga SS. 121. Lani R, Moghaddam E, Haghani A, Chang LY, AbuBakar S, Zandi K. Tick-borne
Brown spiders and loxoscelism. Toxicon. 2004;44(7):693–709. viruses: a review from the perspective of therapeutic approaches. Ticks Tick
97. Magalhães GS, Caporrino MC, Della-Casa MS, Kimura LF, Prezotto-Neto JP, Borne Dis. 2014;5(5):457–65.
Fukuda DA, et al. Cloning, expression and characterization of a 122. Lantos PM, Wormser GP. Chronic coinfections in patients diagnosed with
phospholipase D from Loxosceles gaucho venom gland. Biochimie. chronic lyme disease: a systematic literature review. Am J Med.
2013;95(9):1773–83. 2014;127:1105–10.
98. da Silveira RB, Pigozzo RB, Chaim OM, Appel MH, Dreyfuss JL, Toma L, et al. 123. Greca H, Langoni H, Souza LC. Brazilian spotted fever: a reemergent
Molecular cloning and functional characterization of two isoforms of zoonosis. J Venom Anim Toxins incl Trop Dis. 2008;14(1):3–18.
dermonecrotic toxin from Loxosceles intermedia (brown spider) venom 124. Estrada-Peña A, de la Fuente J. The ecology of ticks and epidemiology of
gland. Biochimie. 2006;88(9):1241–53. tick-borne viral diseases. Antiviral Res. 2014;108:104–28.
99. Trevisan-Silva D, Gremski LH, Chaim OM, da Silveira RB, Meissner GO, 125. Barker SC, Murrel A. Phylogeny, evolution and historical zoogeography of
Mangili OC, et al. Astacin-like metalloproteases are a gene family of toxins ticks: a review of recent progress. Exp Appl Acarol. 2002;28(1–4):55–68.
present in the venom of different species of the brown spider (genus 126. Mans BJ, Neitz AW. Adaptation of ticks to a blood-feeding environment:
Loxosceles). Biochimie. 2010;92(1):21–32. evolution from a functional perspective. Insect Biochem Mol Biol.
100. Trevisan-Silva D, Bednaski AV, Gremski LH, Chaim OM, Veiga SS, Senff-Ribeiro A, 2004;34(1):1–17.
et al. Differential metalloprotease content and activity of three Loxosceles spider 127. Steen NA, Barker SC, Alewood PF. Proteins in the saliva of the Ixodida
venoms revealed using two-dimensional electrophoresis approaches. Toxicon. (ticks): Pharmacological features and biological significance. Toxicon.
2013;76:11–22. 2006;47(1):1–20.
101. Veiga SS, da Silveira RB, Dreyfus JL, Haoach J, Pereira AM, Mangili OC, et al. 128. Cohen SB, Freye JD, Dunlap BG, Dunn JR, Jones TF, Moncayo AC. Host
Identification of high molecular weight serine-proteases in Loxosceles associations of Dermacentor, Amblyomma, and Ixodes (Acari: Ixodidae) ticks
intermedia (Brown spider) venom. Toxicon. 2000;38(6):825–39. in Tennessee. J Med Entomol. 2010;47(3):415–20.
102. Lira-da-Silva RM, Matos GB, Sampaio RO, Nunes TB. Estudo retrospectivo de 129. Buczek A, Olszewski K, Andrearczyk A, Zwoliński J. Morphology of tick tarsus
latrodectismo na Bahia Brasil. Rev Soc Bras Med Trop. 1995;28(3):205–10. (Acari: Ixodia) modifications connected with life cycle, behavior and habitat.
103. Isbister GK, White J. Clinical consequences of spider bites: recent advances Wiad Parazytol. 2004;50(2):285–94.
in our understanding. Toxicon. 2004;43(5):477–92. 130. Mans BJ, Steinmann CM, Venter JD, Louw AI, Neitz AW. Pathogenic
104. Ott R, Rodrigues ENL, Marques MAL. First record of Lactrodectus mirabilis mechanisms of sand tampan toxicoses induced by the tick Ornithodoros
(Araneae: Theridiidae) from southern Brazil and data on natural history of savignyi. Toxicon. 2002;40(7):1007–16.
the species. Rev Colomb Entomol. 2014;40(2):311–6. 131. Mans BJ, Gothe R, Neitz AW. Biochemical perspectives on paralysis and other
105. Camp NE. Black widow spider envenomation. J Emerg Nurs. forms of toxicoses caused by ticks. Parasitology. 2014;129(Suppl):S95–111.
2014;40(2):193–4. 132. Ribeiro JM, Francischetti IM. Role of arthropod saliva in blood feeding:
106. Ushkaryov Y. Alpha-latrotoxin: from structure to some functions. Toxicon. sialome and post-sialome perspectives. Annu Rev Entomol. 2003;48:73–88.
2002;40(1):1–5. 133. Campbell F, Atwell R, Fenning A, Hoey A, Brown L. Cardiovascular effects of
107. Grishin EV, Himmelreich NH, Pluzhnikov KA, Pozdnyakova NG, Storchak LG, the toxin(s) of the Australian paralysis tick, Ixodes holocyclus, in the rat.
Volkova TM, et al. Modulation of functional activities of the neurotoxin from Toxicon. 2004;43(7):743–50.
black widow spider venom. FEBS Lett. 1993;336(2):205–7. 134. Simons SM, De-Sá-Júnior PL, Faria F, Batista IF, Barros-Battesti DM, Labruna
108. Grishin EV. Black widow spiders toxins: the present and the future. Toxicon. MB, et al. The action of Amblyomma cajennense tick saliva in compounds of
1998;36(11):1693–701. the hemostatic system and cytotoxicity in tumor cell lines. Biomed
109. Rohou A, Nield J, Ushkaryov YA. Insecticidal toxins from black widow spider Pharmacother. 2011;65(6):443–50.
venom. Toxicon. 2007;49(4–5):531–49. 135. Drewes CC, Dias RY, Hebeda CB, Simons SM, Barreto SA, Ferreira Junior JM,
110. Danilevich VN, Grishin EV. The cromossomal genes for black widow spider et al. Actions of the Kunitz-type serine protease inhibitor Amblyomin-X on
neurotoxins do not contain introns. Bioorg Khim. 2000;26(12):933–9. VEGF-A-induced angiogenesis. Toxicon. 2012;60(3):333–40.
111. Ushkaryov YA, Petrenko AG, Geppert M, Sudhof TC. Neurexins: synaptic cell 136. Chudzinski-Tavassi AM, De-Sá-Júnior PL, Simons SM, Maria DA, de Souza
surface proteins related to the α-latrotoxin receptor and laminin. Science. Ventura J, Batista IF, et al. A new tick Kunitz type inhibitor, Amblyomin-X,
1992;257(5066):50–6. induces tumor cell death by modulating genes related to the cell cycle and
112. Lelianova VG, Davletov BA, Sterling A, Rahman MA, Grishin EV, Totty NF, et targeting the ubiquitin-proteasome system. Toxicon. 2010;56(7):1145–54.
al. Alpha-latrotoxin receptor, latrophilin, is a novel member of the 137. Nienaber J, Gaspar AR, Neitz AW. Savignin, a potent thrombin inhibitor
secretin family of G protein- coupled receptors. J Biol Chem. isolated from the salivary glands of the tick Ornithodoros savignyi
1997;272(34):21504–8. (Acari: Argasidae). Exp Parasitol. 1999;93(2):82–91.
113. Ushkaryov YA, Volynski KE, Ashton AC. The multiple actions of black widow 138. Mans BJ, Louw AI, Neitz AW. Evolution of hematophagy in ticks: common
spider toxins and their selective use in neurosecretion studies. Toxicon. origins for blood coagulation and platelet aggregation inhibitors from soft
2004;43(5):527–42. ticks of the genus Ornithodoros. Mol Biol Evol. 2002;19(10):1695–705.
114. Ishiwata K, Sasaki G, Ogawa J, Miyata T, Su ZH. Phylogenetic relationships 139. Francischetti IM, Valenzuela JG, Andersen JF, Mather TN, Ribeiro JM. Ixolaris,
among insect orders based on three nuclear protein-coding gene a novel recombinant tissue factor pathway inhibitor (TFPI) from the salivary
sequences. Mol Phylogenet Evol. 2011;58(2):169–80. gland of the tick, Ixodes scapularis: identification of factor X and factor Xa as
Cordeiro et al. Journal of Venomous Animals and Toxins including Tropical Diseases (2015) 21:24 Page 14 of 14

scaffolds for the inhibition of factor VIIa/tissue factor complex. Blood. 166. Liu Z, Liu H, Liu X, Wu X. Purification and cloning of a novel antimicrobial
2002;99(10):3602–12. peptide from salivary glands of the hard tick, Ixodes sinensis. Comp Biochem
140. Ribeiro JM, Alarcon-Chaidez F, Francischetti IM, Mans BJ, Mather TN, Physiol B Biochem Mol Biol. 2008;149(4):557–61.
Valenzuela JG, et al. An annotated catalog of salivary gland transcripts from 167. Pichu S, Ribeiro JM, Mather TN. Purification and characterization of a novel
Ixodes scapularis ticks. Insect Biochem Mol Biol. 2006;36(2):111–29. salivary antimicrobial peptide from the tick Ixodes scapularis. Biochem
141. Narasimhan S, Koski RA, Beaulieu B, Anderson JF, Ramamoorthi N, Kantor F, Biophys Res Commun. 2009;390(3):511–5.
et al. A novel family of anticoagulants from the saliva of Ixodes scapularis. 168. Zheng H, Zhou L, Yang X, Wang D, Liu J. Cloning and characterization of a
Insect Mol Biol. 2002;11(6):641–50. male-specific defensin-like antimicrobial peptide from the tick
142. Waxman L, Smith DE, Arcuri KE, Vlasuk GP. Tick anticoagulant peptide (TAP) Haemaphysalis longicornis. Dev Comp Immunol. 2012;37(1):207–11.
is a novel inhibitor of blood coagulation factor Xa. Science. 1990;248(4955):593–6. 169. Chrudimská T, Slaninová J, Rudenko N, Růžek D, Grubhoffer L. Functional
143. Van de Locht A, Stubbs MT, Bode W, Friedrich T, Bollschweiler C, Höffken W, characterization of two defensing isoforms of the hard tick Ixodes ricinus.
et al. The ornithodorin-thrombin crystal structure, a key to the TAP enigma? Parasit Vectors. 2011;4:63.
EMBO J. 1996;15:6011–7.
144. Lim-Wilby MS, Hallenga K, de Mayer M, Lasters I, Vlasuk GP, Brunck TK. NMR
structure determination of tick anticoagulant peptide (TAP). Protein Sci.
1995;4(2):178–86.
145. Koh CY, Kazimirova M, Trimnell A, Takac P, Labuda M, Nuttall PA, et al.
Variegin, a novel fast and tight binding thrombin inhibitor from the tropical
bont tick. J Biol Chem. 2007;282(40):29101–13.
146. Masina S, Broady KW. Tick paralysis: development of a vaccine. Int J
Parasitol. 1999;29(4):535–41.
147. Crause JC, Verschoor JA, Coetzee J, Hoppe HC, Taljaard JN, Gothe R, et al.
The localization of a paralysis toxin in granules and nuclei of prefed female
Rhipicephalus evertsi evertsi tick salivary gland cells. Exp Appl Acarol.
1993;17(5):357–63.
148. Hall-Mendelin S, Craig SB, Hall RA, O’Donoghue P, Atwell RB, Tulsiani SM, et
al. Tick paralysis in Australia caused by Ixodes holocyclus Neumann. Ann
Trop Med Parasitol. 2011;105(2):95–106.
149. Almeida RAMB, Ferreira MA, Barraviera B, Haddad Jr V. The first reported
case of human tick paralysis in Brazil: a new induction pattern by immature
stages. J Venom Anim Toxins incl Trop Dis. 2012;18(4):459–61.
150. Vink S, Daly NL, Steen N, Craik DJ, Alewood PF. Holocyclotoxin-1, a cystine
knot toxin from Ixodes holocyclus. Toxicon. 2014;90:308–17.
151. Brazier I, Kelman M, Ward MP. The association between landscape and
climate and reported tick paralysis cases in dogs and cats in Australia. Vet
Parasitol. 2014;204(3–4):339–450.
152. Taraschenko OD, Powers KM. Neurotoxin-induced paralysis: a case of tick
paralysis in a 2-year-old child. Pediatr Neurol. 2014;50(6):605–7.
153. Pecina CA. Tick paralysis. Semin Neurol. 2012;32(5):531–2.
154. Purwar S. Tick paralysis: an uncommon dimension of tick-borne diseases.
South Med J. 2009;102(2):131.
155. Edlow JA, McGillicuddy DC. Tick paralysis. Infect Dis Clin North Am.
2008;22(3):397–413.
156. Schull DN, Litster AL, Atwell RB. Tick toxicity in cats caused by Ixodes species in
Australia: a review of published literature. J Feline Med Surg. 2007;9(6):487–93.
157. Vedanarayanan V, Sorey WH, Subramony SH. Tick paralysis. Semin Neurol.
2004;24(2):181–4.
158. Bowman AS, Gengler CL, Surdick MR, Zhu K, Essenberg RC, Sauer JR, et al. A
novel phospholipase A2 activity in saliva of the lone star tick, Amblyomma
americanum (L). Exp Parasitol. 1997;87(2):121–32.
159. Zhu K, Bowman AS, Dillwith JW, Sauer JR. Phospholipase A2 activity in
salivary glands and saliva of the lone star tick (Acari: Ixodidae) during tick
feeding. J Med Entomol. 1998;35:500–4.
160. Rego RO, Kovár V, Kopácek P, Weise C, Man P, Sauman I, et al. The tick
plasma lectin, Dorin M, is a fibrinogen-related molecule. Insect Biochem Mol
Biol. 2006;36(4):291–9.
161. Bautista-Garfias CR, Martínez-Cruz MA, Córdoba-Alva F. Lectin activity from
the cattle tick (Boophilus microplus) saliva. Rev Latinoam Microbiol. Submit your next manuscript to BioMed Central
1997;39(1–2):83–9. and take full advantage of:
162. Rego RO, Hajdusek O, Kovár V, Kopácek P, Grubhoffer L, Hypsa V. Molecular
cloning and comparative analysis of fibrinogen-related proteins from the
• Convenient online submission
soft tick Ornithodoros moubata and the hard tick Ixodes ricinus. Insect
Biochem Mol Biol. 2005;35:991–1004. • Thorough peer review
163. Lai R, Takeuchi H, Lomas LO, Jonczy J, Rigden DJ, Rees HH, et al. A new • No space constraints or color figure charges
type of antimicrobial protein with multiple histidines from the hard tick
Amblyomma hebraeum. FASEB J. 2004;18(12):1447–9. • Immediate publication on acceptance
164. Lai R, Lomas LO, Jonczy J, Turner PC, Rees HH. Two novel non-cationic • Inclusion in PubMed, CAS, Scopus and Google Scholar
defensin-like antimicrobial peptides from haemolymph of the female tick • Research which is freely available for redistribution
Amblyomma hebraeum. Biochem J. 2004;379(Pt 3):681–5.
165. Yu D, Sheng Z, Xu X, Li J, Yang H, Liu Z, et al. A novel antimicrobial peptide
from salivary glands of the hard tick Ixodes sinensis. Peptides. 2006;27(1):31–5. Submit your manuscript at
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