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Review Article
Journal of Translational Science
ISSN: 2059-268X
J Transl Sci, 2021 doi: 10.15761/JTS.1000457 Volume 7: 1-23
Exploring the global animal biodiversity in the search for
new drugs - Reptiles
Dennis R.A. Mans*, Meryll Djotaroeno, Jennifer Pawirodihardjo and Priscilla Friperson
Department of Pharmacology, Faculty of Medical Sciences, Anton de Kom University of Suriname, Paramaribo, Suriname
*Correspondence to: Dennis R.A. Mans. Department of Pharmacology, Faculty
of Medical Sciences, Anton de Kom University of Suriname. Kernkampweg 5-7,
Paramaribo, Suriname, Tel/Fax: +597 441071. E-mail: dennismans16@gmail.
com; dennis_mans@yahoo.com
Key words: lizards, snakes, testudines, crocodilians, venoms, immune system
components, bioactive compounds, novel therapeutics
Received: March 29, 2021; Accepted: April 26, 2021; Published: April 29, 2021
Introduction
New drug discovery and development programs have historically
relied on the identication of novel lead compounds from plant
origin. is is understandable when considering that plants have
been the main, if not the only sources of therapeutics for managing
human diseases for millennia [1]. Only in 1806, a pharmacologically
active ingredient (morphine) from a plant (the opium poppy Papaver
somniferum (Papaveraceae)) was for the rst time isolated from a plant
[2]. Currently, morphine is used for, among others, the palliation of
severe chronic pain in, for instance, terminal cancer patients [2], and
serves as a precursor for a large number of opioid medications such as
the antitussive codeine and the antidiarreal agent loperamide [2]. e
identication of morphine from P. somniferum was soon followed by
many others such as, among others, the central nervous system stimulant
caeine from the beans of the coee plant Coea arabica (Rubiaceae) in
1819 [3], the antimalarial quinine from the bark of the cinchona tree
Cinchona ocinalis (Rubiaceae) in 1820 [4], and the analgesic salicin
from the bark of the white willow Salix alba (Salicaceae) in 1828 [5].
Since then, many more breakthrough drugs have been developed
from plants, including the antineoplastic agents vincristine and
paclitaxel from the periwinkle plant Catharanthus roseus (Apocynaceae)
[6] and the Pacic yew Taxus brevifolia (Taxaceae) [7], respectively;
the phytoestrogen diosgenin from yam species in the genus Dioscorea
(Dioscoreaceae) that serves as a precursor of, among others, oral
contraceptives and cortisone [8]; and the oral antihyperglycemic
biguanide metformin from the French lilac Galega ocinalis (Fabaceae)
[9]. Other important sources of novel drugs were micro-organisms.
e fungus Penicillium rubens (Trichocomaceae) and the actinomycete
bacterial species Saccharopolyspora erythraea (Pseudonocardiaceae)
gave the antibacterial agents penicillin [10] and erythromycin
Abstract
New drug discovery and development eorts have traditionally relied on ethnopharmacological information and have focused on plants with medicinal properties.
In the search for structurally novel and mechanistically unique lead compounds, these programs are increasingly turning to the bioactive molecules provided by
the animal biodiversity. is not only involves bioactive constituents from marine and terrestrial invertebrates such as insects and arthropods, but also those from
amphibians and other ‘higher’ vertebrates such as reptiles. e venoms of lizards and snakes are complex mixtures of dozens of pharmacologically active compounds.
So far, these substances have brought us important drugs such as the angiotensin-converting enzyme inhibitors captopril and its derivates for treating hypertension
and some types of congestive heart failure, and the glucagon-like peptide-1 receptor agonist exenatide for treating type 2 diabetes mellitus. ese drugs have been
developed from the venom of the Brazilian pit viper Bothrops jararaca (Viperidae) and that of the Gila monster Heloderma suspectum (Helodermatidae), respectively.
Subsequently, dozens of potentially therapeutically applicable compounds from lizards’ and snakes’ venom have been identied, several of which are now under clinical
evaluation. Additionally, components of the immune system from these animals, along with those from turtles and crocodilians, have been found to elicit encouraging
activity against various diseases. Like the venoms of lizards and snakes, the immune system of the animals has been rened during millions of years of evolution in order
to increase their evolutionary success. is paper addresses some of the bioactive compounds from reptiles, and elaborates on the therapeutic potential of some of them as
anticoagulants and antiplatelet drugs, as well as wound healing-promoting, antileishmanial, antiviral, immunomodulating, antimicrobial, and anticancer compounds.
[11], respectively. Another bacterial species, Streptomyces nodosus
(Streptomycetaceae), produced the antifungal and antileishmanial agent
amphotericin B [12]. e ascomycete fungus Tolypocladium inatum
(Ophiocordycipitaceae) led to the immunosuppressive agent tacrolimus
[13], and the soil-borne fungus Aspergillus terreus (Trichocomaceae)
produced specic LDL-lowering HMG-CoA reductase-inhibiting
statins such as simvastatin that reduce the risk of arterial blockage, a
heart attack, a stroke, and diabetes mellitus [14].
More recently, investigators in the eld of new drug discovery and
development have also turned to the animal kingdom. is has led to
a number of important drugs such as ziconotide, a powerful analgesic
that was structurally based on the extremely potent conotoxins
produced by predatory cone snails in the genus Conus (Conidae) [15];
and trabectedin, an orphan drug for treating so-tissue sarcomas
and ovarian cancer that was rst identied in the mangrove tunicate
Ecteinascidia turbinata (Perophoridae) [16]. Various reptiles have also
yielded important and life-saving drugs. e angiotensin-converting
enzyme inhibitor captopril and its derivatives for treating hypertension
and some types of congestive heart failure, have been developed from
the venom of the Brazilian viper Bothrops jararaca (Viperidae) [17].
And exenatide for treating type 2 diabetes mellitus was originally
Mans DRA (2021) Exploring the global animal biodiversity in the search for new drugs - Reptiles
J Transl Sci, 2021 doi: 10.15761/JTS.1000457 Volume 7: 2-23
isolated from the venom of the Gila monster Heloderma suspectum
(Helodermatidae) [18] (Figure 1).
In this paper, a number of bioactive compounds from several
members of the reptilian suborders Lacertilla (lizards) and Serpentes
(snakes) - both belonging to the order Squamata or scaled reptiles
- as well as the orders Testudines (turtles and alike) and Crocodylia
(crocodiles and alike) have extensively been addressed for their
potential as clinically useful drugs. e fourth reptilian order, the
Rhynchocephalia (tuataras), and the squamate suborder Amphisbaenia
(worm lizards) have been le out of this paper because of the lack of
literature data on their potential medical applicability. Each of these
sections is preceded by background information about the (sub)order
that is dealt with. e paper is concluded with some remarks about the
previsions of reptilian bioactive compounds for new drug development
programs.
Background
Evolutionary development of reptiles: Reptiles are a class of
tetrapod animals that possess scaly skin and lungs, are ectotherms, and
lay shelled eggs on land. ey comprise the extant lizards, snakes, and
worm lizards; turtles, tortoises, and terrapins; crocodiles, alligators,
caimans, and gharials; tuataras; as well as their extinct relatives [19].
ese animals probably originated from advanced reptiliomorphs
during the Carboniferous period, 360 to 300 million years ago [20].
Because these reptiliomorphan ancestors had four legs, reptiles are
classied as tetrapods despite the existence of species with vestigial
limbs and a limbless appearance such as snakes [21]. e skin of reptiles
is covered with a continuous layer of scales containing keratin and waxy
lipids which help reduce water loss from the body and represented an
important adaptation that permitted them to live on land [22]. On the
other hand, the occlusive skin prohibits cutaneous respiration like in
amphibians, necessitating the development of ecient lungs [23].
e ability of reptiles to produce terrestrially-adapted eggs enclosed
in an amnion and protected by a hard outer shell can be regarded as
one of the monumental events in the Earth’s evolution, and certainly
one of the main determining factors for the evolutionary success of
these animals. is made them, unlike their immediate predecessors,
the amphibians, independent of water for their reproduction. Notably,
even aquatic reptiles return to land to lay eggs [24], whereas land-
adapted amphibia search for water to lay their vulnerable shell-less eggs
in order to ensure ospring [25]. e shell of the reptilian egg provides
protection for the developing embryo and allows water retention
while being permeable for gas exchange [24]. Inside, the embryo is
surrounded by the amnion, a membrane that forms a uid-lled sac
in which the embryo is suspended in its own aquatic environment
[24]. ese advantages allowed the early reptiles to branch out to drier
environments and enabled them to fully colonize many terrestrial
niches [24].
Until the Late Carboniferous, around 310 million years ago, the
early reptile-like amniotes represented a small, unremarkable group
when compared to their much more numerous amphibian ancestors
which then dominated terrestrial life on Earth [26]. is radically
changed with the occurrence of the Carboniferous Rainforest Collapse
305 million years ago and the Permian-Triassic extinction event 54
million years later, the largest-ever extinction event on Earth [27]. e
Carboniferous Rainforest Collapse was a relatively minor extinction
event that was characterized by global warming and the destruction
of large parts of the tropical rain forests that then covered the former
supercontinent Euramerica [27]. e subsequent Permian-Triassic
mass extinction event, colloquially referred to as the the Great
Dying, wiped out 90 to 96% of all forms of life that had survived the
Carboniferous Rainforest Collapse [27,28]. e all-out winners were
the relatively few surviving reptiles which were able to produce hard-
shelled amniotic eggs under those harsh and drier conditions [28]. As
a result, they could thrive, diversify, occupy vacant ecological niches,
and replace the amphibians as the dominant tetrapods [29]. is was
the basis of the ‘rise of the reptiles’ which reached its pinnacle during
the Mesozoicum (Triassic, Jurassic, and Cretaceous), 252 to 66 million
years ago, the geological period referred to as the Age of Reptiles [29].
Characteristics of reptiles: As mentioned above, the modern
reptiles comprise a class of ectothermic, tetrapod vertebrates that
lay shelled eggs on land, possess scales on their skin which protect
them from desiccation, breathe through lungs, make use of internal
fertilization, and have amniotic development. Belonging to the
superclass Tetrapoda, reptiles have in principle four legs that project
sideways from the body [21]. Snakes as well as legless lizards in the
family Anguidae (slowworms) have completely lost their limbs during
evolution and move by using their ventral scales and ribs [30]. Hence
the name ‘Reptilia’ of this animal class, which is derived from the
Latin expressions ‘reptilis’ and ‘rēpō’, meaning ‘creeping’ and ‘to creep’,
respectively, obviously referring to the fact that many crawl by moving
on their belly or by means of small and short legs. Reptiles can be found
everywhere on Earth, particularly in temperate and tropical regions.
Most reptiles live on land but some species, such as those in the order
Crocodylia, are amphibious, living both in water and on land.
Like other ectotherms, reptiles use relatively little of their metabolic
energy from food to sustain their bodily functions and are able to
survive on about 10% of the calories required by similarly-sized
endotherms [31]. On the other hand, reptiles have to rely on the
environment as their main source of body heat instead of generating
heat by their own metabolism as endotherms do [32]. For this purpose,
they have developed behavioral adaptations to help regulate their
body temperature, such as basking in sunny places to warm up, and
nding shady spots or going underground to cool down [32]. Under
extreme environmental conditions, some reptiles may enter periods
of dormancy, temporarily stopping their growth, development, and
physical activity, thus minimizing metabolic activity and conserving
energy. For instance, in response to very hot or dry conditions, North
American desert tortoises and certain species of crocodiles may enter a
Figure 1. The Gila monster Heloderma suspectum (Helodermatidae) (from: https://images.
app.goo.gl/dPs91WnmiHayS6S36)
Mans DRA (2021) Exploring the global animal biodiversity in the search for new drugs - Reptiles
J Transl Sci, 2021 doi: 10.15761/JTS.1000457 Volume 7: 3-23
period of estivation [33], while certain lizards, tortoises, turtles, frogs,
and snakes brumate in very cold temperatures [33].
In lizards, snakes, and tuataras, the non-permeable, watertight skin
is entirely covered with overlapping epidermal scales [22]. e shells of
turtles and the plates of crocodiles are covered by scutes which are of
dermal rather than epidermal origin and are fused to tough, protective
armor [22]. Reptiles continuously shed their skin during their lifetime
through ecdysis, involving the formation of a new layer of skin under
the old one, and the separation of the old skin from the new one with
the aid of proteolytic enzymes and lymphatic uid [22]. e shells from
turtles, tortoises, and terrapins do not undergo ecdysis since they are
made up of about y bones of their skeleton including their spines
and rib cage and grow with the animals [22]. However, the scutes on
the surface of the shells shed or peel away to make way for newer,
larger scutes [22]. e scales of some reptile species are colored for
camouage or aposetism. Well-known examples are the Madagascan
satanic leaf-tailed gecko Uroplatus phantasticus (Gekkonidae) that
can rapidly change its body color to better match its environment,
avoiding being spotted by an approaching predator or a potential prey
[34,35]; the highly venomous New World coral snakes in the family
Elapidae (Figure 2) which advertise their poisonousness with vividly
red, yellow/white, and black aposematic colored banding [36]; and the
non-venomous Mexican milk snake Lampropeltis triangulum annulata
(Colubridae) that mimics the warning coloration of coral snakes [37].
Most reptiles breathe through lungs which occupy a much
smaller area of the body when compared to mammals but are larger
than those of amphibians [23]. ere are usually two lungs with the
exception of snakes in which the le lung is rudimentary or has even
entirely disappeared [23]. Most squamates and testudines have a three-
chambered heart consisting of two atria and a ventricle, and two aortas
leading to the systemic circulation [38]. Crocodilians have a four-
chambered heart, similarly to birds, but also have two systemic aortas
[38]. e blood is ltered by two relatively small kidneys and the urine
is stored in a urinary bladder. In most species, uric acid is the main
nitrogenous waste product [39]. e main exceptions are aquatic turtles
which excrete most of their nitrogenous wastes as urea or ammonia
[39]. In all reptiles, the urinogenital ducts empty into a cloaca along
with the anus [39].
Most reptiles are carnivorous or insectivorous. As their meals are
fairly simple to break down and digest, they have in general relatively
simple and comparatively short digestive tracts [40]. However, being
poikilotherms and because of their inability to masticate their food,
digestion occurs slower than in mammals [40]. Turtles as well as some
agamas and iguanas are the only groups of reptiles that are mostly
herbivorous. ey also ingest their meals whole but regularly swallow
gastroliths to aid in digestion. Interestingly, salt water crocodiles are
carnivorious but also use gastroliths, not to aid in the digestion of plant
matter but as ballast to help stabilize them in the water or helping them
to dive [41].
Like that of amphibians, the nervous system of reptilians basically
consists of a central brain made up of a forebrain, a midbrain, and a
hindbrain, as well as a spinal cord and nerves throughout the body
including twelve pairs of cranial nerves [42]. As most reptiles are diurnal
carnivorous hunters, they usually have excellent vision, allowing them
to sharply detect colors (including ultraviolet wavelengths), shapes,
motions, and depth at long distances [43]. Many snakes have a ‘third
eye’ (the pineal gland) on the top of their head that cannot form images
but is sensitive to changes in light and dark and can detect movement
[43]. In addition, some snakes such as pit vipers, but also boas as well
as pythons, have pits on both sides of the head behind the nostril and
in front of the eye that are sensitive to infrared radiation, allowing them
to sense the body heat of prey and to hunt in the dark (Figure 3) [44].
Many reptiles use chemically sensitive organs located in the nose
and the roof of the mouth to nd their prey [45]. Part of the epithelium
of the nose consists of olfactory sensory cells for detecting airborne
odors similarly to other vertebrates [45]. ere is oen a second
chemoreceptor in the roof of the mouth - Jacobson’s organ - that serves
as a short-range chemoreceptor of non-airborne odors [46]. Notably,
the nerve connecting Jacobson’s organ to the brain is a branch of the
olfactory nerve [46]. e use of Jacobson’s organ is most obvious in
snakes, which rapidly ick their tongue in and out and transfer with
each retraction odor particles adhering to the tongue to the roof of the
mouth near the opening of the organ.
Reptiles reproduce sexually, although some species are capable of
asexual reproduction [47]. e male specimens of snakes and lizards
have paired copulatory organs known as hemipenes which are situated
in a pouch at the base of the tail just caudal to the cloaca [48]. ese
organs engorge with sexual excitement and only one is used in each
session to penetrate the cloaca of the female and deposit semen [48].
Male turtles and crocodilians have a single median phallus [48]. Tuatara
lack copulatory organs and mating occurs by appositioning of the
cloacae of the male and the female as the male discharges sperm [48].
All turtles, crocodiles, and tuataras as well as some species of lizard and
snake are oviparous [47]. Sea snakes, garter snakes, boas, pit vipers, and
spitting cobras, as well as skinks and night lizards have placenta-like
structures capable of transferring nutrients to the foetus, give birth to
live young, and are thus viviparous [47]. And slowworms, the antenatal
anaconda, and the adder are ovoviviparous, i.e., the embryos develop
inside eggs that remain in the mother’s body until they are ready to
hatch, but the foetus is not sustained through a placenta but from the
egg [47]. Asexual reproduction by parthenogenesis has been described
in the lizard families of racerunners, wall lizards, dragon lizards, and
chameleons, as well as in the family of blind snakes [49].
Classication of reptilia: As of December 2020, the class Reptilia
comprised 4 orders, 92 families, 1,216 genera, and 11,440 species [19].
e 4 orders are the Squamata, the Testudines, the Crocodylia, and the
Rhynchocephalia (Scheme 1) [19]. e Squamata represents the largest
reptilian order, encompassing over 11,000 known species or more than
Figure 2. Aquatic coral snake Micrurus surinamensis (Elapidae) (from: https://images.app.
goo.gl/ZPUuV2RzTzkUufaB7)
Mans DRA (2021) Exploring the global animal biodiversity in the search for new drugs - Reptiles
J Transl Sci, 2021 doi: 10.15761/JTS.1000457 Volume 7: 4-23
95% of all known reptiles [19]. e Squamata include 3 suborders, the
Lacertilia (lizards, 6,972 species), the Serpentes (snakes, 3,879 species),
and the Amphisbaenia (worm lizards; 201 species) (Scheme 1), although
some classications place the Amphisbaena within the Lacertilia [19].
Based on archeological nds, the origin of the Squamata has been
dated to the Early Triassic, 251.9 to 247.2 million years ago [50,51].
e name ‘Squamata’ is derived from the Latin word ‘squamatus’ for
‘scaly’ and ‘having scales’, referring to a distinguishing characteristic of
this reptilian order, the horny scales or shields they bear on their skin
[22]. Another typical feature of squamates is the presence of movable
quadrate bones, enabling them to move the upper jaw relative to the
neurocranium [52]. is is most evident in snakes, which are able
to open their mouth very wide to accommodate comparatively large
prey [52]. e Squamata are also characterized by the presence of two
hemipenes in the male members [48] and the production of ospring
by both viviparity and ovoviviparity in addition to the usual oviparity
in most reptiles [47].
e Testudines, also referred to as Chelonia, comprise 361 species
of turtles, tortoises, and terrapins, and represent about 3% of all
reptiles [19]. Like other reptiles, these animals are ectothermic, have
scales covering their skin, breathe through lungs, and lay eggs on land.
However, unique to the Testudines is the bony or cartilaginous shell
developed from their ribs and other parts of their skeleton that encases
their bodies, acting as a shield [22]. Testudines are among the oldest
reptile groups, more ancient than snakes or crocodilians, their earliest
known members dating from the Middle Jurassic, 174.1 to 163.5 million
years ago [53]. An important aspect of their reproductive biology is the
ability of the females to store viable sperm in their oviducts for long
periods of time [54].
e Crocodylia comprise an order of large, predatory, semi‐aquatic
reptiles which encompass 26 known species of crocodiles, alligators,
caimans, and gharials [19]. ey represent roughly 0.3% of all living
reptile species [19]. Crocodilians rst appeared 95 million years ago
in the Late Cretaceous period (145 to 66 million years ago) and are
the closest living relatives of birds [55]. Crocodilians have a unique
body form that allows the eyes, ears, and nostrils to be above the water
surface while the rest of the animal is hidden below [56]. e tail is
long and robust, the skin is covered with bony scales, and the back is
protected by thick, bony plates, enabling them to withstand harsh, dry
conditions and to survive in both land and water [56]. e relatively
long snout varies considerably in shape and proportion among families
and genera [56].
e Rhynchocephalia or tuataras represent the smallest reptilian
order, measuring up to 80 centimeters and weighing about 1 kilogram,
and harboring only two living lizard-like (sub)species, S. punctatus
punctatus and S. punctatus guntheri (Sphenodontidae) [19]. ey arose
during the Age of Reptiles in the Mesozoic era, 252 to 66 million years
ago [50], and are currenty only found in small, relatively inaccesible,
islands o the coast of New Zealand [57]. Although resembling lizards,
several unique features of the skull and jaws clearly distinguish tuataras
from squamates. Firstly, their dentition is unique among living species,
consisting of two rows of teeth in the upper jaw that overlap one row
on the lower jaw [58]. Secondly, they possess a third eye on the top
of the head with a retina, lens, and nerve endings [58]. is so-called
parietal eye is only visible in hatchlings and becomes covered in scales
and pigments aer four to six months, and is not used for vision but to
help judge the time of day or season [59]. Tuataras are the sole surviving
members of the Rhynchocephalia which was well represented by many
species during the age of the dinosaurs in the Mesozoic, some 200
million years ago [58].
Lizards
Generalities about lizards: e squamate suborder Lacertilia
or Sauria, commonly known as lizards, is a widespread group of
scaled reptiles consisting of almost 7,000 extant species in 55 families
and subfamiles [19]. Well-known lizard species that are extensively
addressed further in this section are the Gila monsters in the family
Helodermatidae and the monitor lizards in the family Varanidae [19].
e names ‘Lacertilia’ and ‘Sauria’ of this reptilian suborder are derived
from the Latin words ‘lacerta’ for ‘lizard’ and ‘ilia’ for ‘similar to’, and
the Ancient Greek word ‘saûros’ or ‘saúra’ for ‘lizard’ or ‘reptile’. Among
the smallest species of lizard are the dwarf geckoes Sphaerodactylus
ariasae and S. parthenopion from the Dominican Republic and the
Virgin Islands, respectively, both in the family Sphaerodactylidae and
measuring 1.6 to 2.0 centimeters from the snout to the base of the
tail [60], as well as the 2- to 3-centimeters long Madagascan dwarf
chameleon Brookesia micra (Chamaeleonidae) [61]. e largest lizard
is the 3-meters long and approximately 70-kilograms heavy Komodo
dragon Varanus komodoensis (Varanidae) found in Indonesia [62]
(Figure 4).
A characteristic of lizards (that they share with snakes) is the
movable quadrate bone, dierentiating them from tuataras which
have more rigid diapsid skulls [50]. Most lizards have rounded torsos,
elevated heads on short necks, long tails, and four limbs, alternatingly
Figure 3. Pit viper with clearly visible pit located between the eye and the nostril (from:
https://images.app.goo.gl/GDtm464p7zZ2oHBw6)
Kingdom: Animalia (animals)
Phylum: Chordata
Class: Reptilia
Order: Squamata
Suborders: Lacertilla (lizards)
Serpentes (snakes)
Amphisbaenids (worm-lizards)
Order: Testudines (turtles, tortoises, and terrapins)
Suborders: Pleurodirans
Cryptodirans
Order: Crocodylia
Family: Crocodylidae (crocodiles)
Alligatoridae (caimans and alligators)
Gavialidae (gharials)
Order: Rhynchocephalia (Sphenodontia)
Family: Tuataras (Sphenodons)
Scheme 1. Taxonomy of reptilia
Mans DRA (2021) Exploring the global animal biodiversity in the search for new drugs - Reptiles
J Transl Sci, 2021 doi: 10.15761/JTS.1000457 Volume 7: 5-23
using the right and le ones, resulting in a typical side-to-side
locomotion. Some, such as the slowworm Anguis fragilis (Anguidae)
are legless, and have long snake-like bodies [63]. Others such as the
forest-dwelling ying lizards in the genus Draco (Agamidae) are able to
glide over distances as far as sixty meters [64]. Still other species such
as geckoes (Gekkota) and chameleons (Chamaeleonidae), can adhere to
smooth vertical surfaces including glass and ceilings by using adhesive
pads with millions of tiny hair-like structures with the aid of van der
Waals forces [65]. And when eeing from predators, basilisk lizards in
the genus Basiliscus (Corytophanidae) can gather sucient momentum
to run across water for a brief distance while holding most of their body
out of the water [66].
Lizards are found on all continents, particularly in tropical
habitats where they mainly live on the ground, in rocks, on trees, and
underground [19]. However, they are highly adaptable and can be
encountered in rather extreme environments with the exception of
Antarctica and most oceanic island chains [19]. For instance, the red
tail toad-headed lizard Phrynocephalus erythrurus (Agamidae) lives
on the Qiangtang Plateau in northern Tibet at a height of 4.5 to 5.3
kilometers above sea level [67]. And the marine iguana Amblyrhynchus
cristatus (Iguanidae) from the Galápagos Islands is completely adapted
to sea where it almost exclusively feeds on algae [68].
All lizards possess senses of sight, touch, olfaction, and hearing
like other vertebrates, but depending on the habitat they live in, a
particular sense is more prominently developed. For instance, fossorial
skinks heavily rely on olfaction and touch [69], while geckoes largely
depend on acute vision to hunt and to estimate the distance to their
prey before striking [70]. Lizards make use of internal fertilization, and
copulation involves the male inserting one of its hemipenes into the
female’s cloaca [48]. e majority of species is oviparous, parental care
is uncommon and the female usually abandons the eggs aer laying
them. Various species of racerunners in the family Teiidae reproduce
by parthenogenesis, i.e., the production of young from unfertilized eggs
[71].
Most lizards are carnivorous, preying on a large variety of animals
ranging from insects to larger vertebrates [72]. In their turn, many
lizards are preyed on by, among others, hawks, owls and eagles, as
well as snakes, weasels, and even larger species of lizards [72]. For
these reasons, they have developed a number of eective defensive
mechanisms. ese involve, among others, trying to outrun a predator
or escape into a hole or a crack [73]; inating their body to resemble an
intimidating spiny balloon [74]; playing dead [75]; squirting a stream
of foul-tasting blood from a pouch beneath their eyes on the opponent
[76]; changing the colors and patterns on their skin to resemble their
surroundings [77]; and autotomize their tail to distract the opponent
and create an opportunity to ee [78].
In addition, some lizards in the family Helodermatidae (such as
the Gila monster H. suspectum as well as the Mexican beaded lizard
H. horridum and the Guatemalan beaded lizard H. charlesbogerti)
and some monitor lizards in the genus Varanus (such as the Komodo
dragon V. komodoensis, the spotted tree monitor V. s ca l a r i s, and the
lace monitor V. v a r i u s ) use venom to subdue their prey and defend
themselves [79-81]. Unlike snakes which produce venom in their upper
jaw [79-81], these lizards produce venom in modied salivary glands in
their lower jaw [79-81]. Each gland has a separate duct leading to the
base of the teeth, and the venom is delivered to the victim by chewing
on the wound caused by biting [79-81]. Furthermore, monitor lizards
feed on a broad spectrum of food items including decaying animals
[82], and their saliva contains highly septic bacteria which are also
delivered to bitten prey and predators [83,84]. However, these animals
regularly engage in vicious territorial ghts [85], sometimes inicting
serious wounds on each other which do not seem to cause serious harm
[86]. is has led to the hypothesis that varanids have a robust innate
immune system that protects them against potential sepsis due to bites
from other monitor lizards [86].
Bioactive compounds from lizards: Lizards have been used for
centuries in the ethnomedical practices of various societies throughout
the world. Medieval manuscripts from Azerbaijan mention the use
of the Caucasian agama Paralaudakia caucasia (Agamidae) and the
common wall gecko Tarentola mauritanica (Phyllodactylidae) for
treating, among others, leprosy and sexual impotence [87]. e oil
extracted from the fat of spiny-tailed lizards in the genus Uromastyx
(Agamidae) also has a long use as a topical cure for impotence and as
an aphrodisiac in regions in northern Africa and India [88]. Other parts
and products from these lizard species are promoted in Malaysia as a
treatment for over twenty diseases including diabetes mellitus, heart
disease, hypertension, gout, kidney problems, and sexual dysfunction
[89]. In traditional Chinese medicine, toad-head agamas in the genus
Phrynocephalus (Agamidae) are dried and crushed and also used to
treat, among others, erectile dysfunction [90]. In Mozambique, the
tails from chameleons are processed into a medicinal preparation
against asthma [91]. And in some, communities the meat and blood
from various monitor lizards is consumed to promote strength, vitality,
stamina, and sexual drive [92].
e venom of helodermatid and varanid lizards contains a large
variety of proteins and peptides including helokinestatins, exendins,
kallikreins, natriuretic peptides, serotonin, phospholipases A2 (PLA2s),
three-nger toxin-like peptides (3FTXs), cysteine-rich secretory
proteins (CRiSPS), and hyaluronidases [79-81]. ese compounds,
both alone and together, are responsible for the tissue breakdown,
inammation, edema, hypothermia, hypotension, peripheral smooth
muscle paralysis, promotion of brinogen cleavage, inhibition of
platelet aggregation, and continuous bleeding following a bite of one
of these animals [79-81]. us, the venoms of these lizard species
represent rich sources of pharmacologically active compounds.
Recognizing this, the venom of the Gila monster H. suspectum
has thoroughly been investigated, which resulted in the identication
of the 39-amino acid peptide exendin-4 that reduced fasting and
postprandial blood glucose in patients with type 2 diabetes mellitus
[18]. Exendin-4 appeared to improve β-cell sensitivity to glucose and to
act as an agonist of glucagon-like peptide 1 (GLP-1), a hormone from
the digestive tract that helps regulate insulin and glucagon secretion
[18]. Subsequent eorts led, as mentioned before, to the development
of the synthetic exendin-4 analogue exenatide (Byetta®), the rst GLP-
1 agonist for managing type 2 diabetes mellitus [18]. Similarly, the
anticoagulant activities in monitor lizards’ venom and components of
the resilient innate immune system of these animals may represent new
lead compounds for treating thrombotic disorders and novel antiseptic
wound healing-stimulating compounds, respectively.
Anticoagulants and antiplatelet drugs from monitor lizards:
Hemostasis is a complex and intricately regulated process that provides
the body the ability to rapidly stop bleeding aer injury in order to
prevent extensive blood loss and infection [93]. To this end, multiple
components of the blood clotting system are activated in response to
damage to blood vessels [93]. is occurs in a series of events that
includes platelet aggregation and blood vessel constriction to stop the
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bleeding; the formation of a plug consisting of platelets, brin, and blood
cells to block further blood loss; and the breakdown of the brin clot
(brinolysis) once the wound has healed [93]. In a healthy individual,
clotting and brinolysis are balanced, i.e., the blood develops clots and
breaks them down exactly when needed. A too low clotting rate in the
blood results in bleeding disorders such as hemophilias, clotting factor
deciencies, von Willebrand disease, hypercoagulable states, and deep
venous thrombosis [94]. On the other hand, increased clotting of the
blood can lead to the formation of dangerous clots in the blood vessels
and the development of thrombotic disorders such as coronary artery
disease, deep vein thrombosis, ischemic stroke, myocardial infarction,
pulmonary embolism, and heart failure [95].
e latter conditions can be treated with anticoagulants
or antiplatelet drugs [96]. Anticoagulants prolong the clotting time,
thereby reducing brin formation, while antiplatelet drugs prevent the
aggregation of platelets [96]. However, in the end, both classes of drugs
prevent clots from forming and increasing in size, reducing the risk
of circulation blockage and a heart attack or a stroke [96]. Examples
of anticoagulants are vitamin K antagonists such as warfarin, direct
thrombin inhibitors such as dabigatran, direct factor Xa inhibitors
such as apixaban, and low-molecular weight heparin anticoagulants
such as dalteparin [96]. Some commonly used antiplatelet drugs are
glycoprotein platelet inhibitors such as eptibatide (that has been
derived from a protein in the venom of the southeastern pygmy
rattlesnake Sistrurus miliarius barbouri (Viperidae) [97]), as well as
platelet aggregation inhibitors such as aspirin, and protease-activated
receptor-1 antagonists like vorapaxar [96].
As mentioned above, varanid lizards’ venom has the capacity
to prevent blood from clotting. Converging lines of evidence have
indicated that this takes place through at least two mechanisms, namely
by cleaving brinogen and by blocking platelet aggregation. Support
for the former mechanism is provided by the capacity of the venom
from various species of Varanus to cleave brinogen [98]. However,
this process occurs dierently from that normally done by thrombin
to produce a clot to cover a wound [98]. Using thromboelastography,
the Varanus venom was observed to cause the brin chains to crosslink
erroneously, producing a non-functional clot in a process called
destructive, non-clotting cleavage [81,99].
Evidence for antiplatelet activity of varanid lizards’ venom came
from the potent blocking eects of the venoms from the lace monitor V.
varius and the Komodo dragon V. komodoensis on platelet aggregation
and blood clotting [80,100,101]. ese activities have been attributed
to (type III) PLA2s in the venoms of the animals [102] which have
been found to promote bleeding and inhibit platelet aggregation
[100,101,103]. PLA2s have been reported to remove, among others,
the fatty acid from the second position of the glycerol backbone of
phospholipids including arachidonic acid, inhibiting the biosynthesis
of thromboxanes by platelets and in this way, the formation of thrombi
[104].
Although preliminary, these observations suggest that the
coagulotoxic compounds in the venom from varanid lizards may
represent potential new lead compounds for designing and developing
novel drugs for treating blood clotting disorders. Importantly, although
helodermatid lizards’ venom may also have this capacity, varanid lizards’
venom is for various reasons believed to be preferable for this purpose.
Firstly, as mentioned above, varanid lizards’ venom probably prevents
blood clotting by cleaving brinogen ánd blocking platelet aggregation
[98-103] while helodermatid lizerds’ venom only exerts antiplatelet
activity [105]. Secondly, the venom from varanid lizard species is
extremely diverse and complex [49] while that from helodermatid
lizard species is probably highly conserved [106], presumably because
of the much larger global variation in ecological niches and prey utilized
by the former species when compared to the latter [80]. us, varanid
lizards’ venoms may comprise a richer variety of toxins for stopping
blood from clotting when compared to those from helodermatid
lizard species, presenting the opportunity to develop a range of new
anticoagulants and/or antiplatelet compounds with dierent potencies.
Wound healing-promoting compounds from monitor lizards: A
wound can be described as the loss or the disruption of the cellular,
anatomical, and functional continuity of living tissues as a result
of trauma [107]. Wounds can be classied as open wounds such as
incisions, lacerations, and abrasions, and closed wounds such as crush
injuries and various types of hematomas [108]. Wounds can also be
distinguished according to the level of microbial contamination, i.e.,
clean wounds, contaminated wounds, infected wounds, and colonized
wounds [109]. Obviously, wounds that are abundantly infected with
bacteria can seriously impede the healing process and can result in life-
threatening complications [109].
e body deals with a lesion by setting into motion a cascade
of events with the aim to repair the injured tissues. is involves a
complex and dynamic, but highly regulated cascade of biochemical
and cellular events that entails four overlapping phases: hemostasis;
inammation; proliferation; and maturation and remodelling [107].
Hemostasis involves the formation of a brin clot by the aggregation
of thrombocytes [107]. During inammation, bacteria and cell debris
are removed by white blood cells [107]. In the proliferation phase, the
wound begins to close as the wound area is rebuild with new granulation
tissue (largely consisting of collagen and extracellular matrix) that is
revascularized by inltrating blood vessels and subsequently covered by
epithelial cells [107]. And during maturation and remodelling, newly
formed collagen increases tensile strength to the wound area while
cellular and angiogenic activities cease [107].
e orderly and timely manifestation of these processes is
imperative to restore the anatomic and functional integrity of the
injured site [107]. us, failure at any stage in the wound healing
process may result in the development of chronic wounds, i.e., wounds
that do not heal spontaneously within three months [110]. Examples
of such wounds are diabetic, vascular, and pressure ulcers, and they
represent an increasing burden to patients, their families, health care
professionals, and health care systems [111]. is is for an important
part due to the rising global incidence of conditions that impede wound
healing such as diabetes mellitus, obesity, and vascular disorders [111].
For this reason, chronic wounds are anticipated to become important
public health concerns of the near future [111].
ere are various options for managing chronic wounds, including
several forms of debridement and the use of antiseptics and antibiotics;
stimulation of the intrinsic process of wound healing using, among
others, growth factors and cytokines; as well as wound support with
proper dressings until the wound area has closed [112]. Several lines
of evidence suggest that compounds in monitor lizards’ blood plasma
may also be useful for managing wounds. is supposition is mainly
based on the various above-mentioned studies reporting no obvious
harm in monitor lizards which have received bacteria-laden bites
from conspecics [83,84]. is suggests that these animals possess a
robust innate immune system, allowing them to eectively deal with
the inammatory phase of the wound healing cascade, preventing the
development of chronic wounds.
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Indeed, the serum of the Komodo dragon V. komodoensis potently
and rapidly inhibited the growth of cultures of the potentially pathogenic
bacterial strains Streptococcus epidermitis, Salmonella typhimurium,
Providencia stuartii, and Shigella exneri, and moderately to strongly
those of Escherichia coli, Staphylococcus aureus, and Klebsiella oxytoca
[86]. ese activities could be ascribed, at least partly, to the powerful
antimicrobial peptide VK25 in the blood plasma of V. komodoensis
[113]. A synthetic analog of VK25 designated DRGN-1 eectively
killed cultured drug-resistant strains of Pseudomonas aeruginosa and S.
aureus by permeabilizing their plasma membrane [113]. DRGN-1 also
substantially promoted tissue regeneration in both uninfected wounds
and biolm wounds in BALB/c mice composed of P. aeruginosa and
S. aureus [113], and stimulated the migration of HEKa keratinocytes
in a scratch-wound closure assay, possibly through activation of the
EGFR/STAT1/3 pathway [113]. Interestingly, among forty-eight novel
potential cationic antimicrobial peptides identied in V. komodoensis
plasma, seven exhibited activity against P. aeruginosa and S. aureus
[114]. Notably, the sequencing, assembly and analysis of the genome
of V. komodoensis revealed the presence of a variety of genes with
important roles in host-defense and innate immunity, many of which
were present in clusters, supporting a robust innate immune system of
these animals [115]. ese insights and developments raise the hope
to identify varanidian antimicrobial peptides that can be used as novel
treatments for chronic wounds.
Snakes
Generalities about snakes: e squamate suborder Serpentes or
snakes comprises about 3,900 species in 30 families of ectothermic,
amniote reptilians with elongated, legless bodies that move creeping
on the oor [19]. A few well-known snake families are the Pythonidae
(pythons), Boidae (boas), Colubridae (colubrids), Elapidae (elapids),
and Viperidae (vipers and pit vipers). e name ‘Serpentes’ of this
reptilian suborder comes from the Latin word ‘serpĕre’ meaning
‘to creep’. However, some species retain a pelvic girdle with a pair of
vestigial claws on either side of the cloaca [21]. Although belonging
to the same order as lizards, snakes lack the eyelids and external ears
present in lizards [116]. As mentioned before, snakes also have very
exible skulls because of the presence of several rotational joints and
mandibles, enabling them to swallow prey much larger than their head
[52]. To accommodate their narrow bodies, snakes’ paired organs (such
as kidneys) are positioned in front of each other instead of side by side,
and most species have only one functional lung [117].
Snakes are encountered on every continent in almost all temperate
to tropical terrestrial and aquatic habitats including deserts, forests (on
the ground as well as in trees), oceans, streams, and lakes, but also in
unusual locations. For instance, the Himalayan keelback Herpetoreas
platyceps (Colubridae), the Himalayan pit viper Gloydius himalayanus
(Viperidae), and the Tibetan hot-spring snake ermophis baileyi
(Colubridae) can be found in the Himalaya Mountains in habitats over
3,000 meters elevation [118-120]. ere are also completely pelagic
snakes such as the venomous yellow-bellied sea snake Hydrophis
platurus (Elapidae) [121] and the coral reef snakes in the subfamily
Hydrophiinae (Elapidae) which are widespread throughout the Indian
and Pacic Oceans [121].
Several lines of evidence suggest that snakes have probably
descended from burrowing lizards during the Cretaceous Period,
145 to 66 million years ago [122]. ese subterranean ancestors of
snakes evolved bodies streamlined for burrowing, eventually became
limbless, and developed a brille (the transparent scales covering the
eyes) and lost their external ears to cope with dirt and damage to
corneas and ears [122]. e smallest known species of snake is the tiny,
10.4 centimeters-long Barbados thread snake Tetracheilostoma carlae
(Leptotyphlopidae) [123]. Among the largest species are the reticulated
python Malayopython reticulatus (Pythonidae) from South Asia and
Southeast Asia, with an average length of 6.5 meters and an average
weight of 59 kilograms [124], the Burmese python Python bivittatus
(Pythonidae) that can become 5 meters long and weigh 75 kilograms
[125], and the South American green anaconda Eunectes murinus
(Boidae) that can reach a length of up to 5.21 meters and a weight of 30
to 70 kilograms [126].
Snakes mainly locate prey and predators by smell, using their forked
tongues to detect airborne particles and passing them to Jacobson’s organ
[46]. Pit vipers, some boas, and pythons can detect warm-blooded prey
and predators using their ‘pits’ [44]. Vision is of secondary importance
in most snakes, only allowing the animals to track movements [127].
As a general rule, vision is best in arboreal snakes and weakest in
burrowing snakes [127]. Furthermore, snakes lack external ears and
eardrums but have fully formed inner ear structures which allows them
to detect vibrations traveling through the ground [128].
Like lizards, snakes employ internal fertilization for their
reproduction, copulation involving the male inserting one of its forked
hemipenes into the female’s cloaca [48]. Most species of snake lay eggs
which they abandon shortly aer laying [129]. Ring-necked spitting
cobras in the genus Hemachatus (Elapidae), garter snakes in the genus
amnophis (Colubridae), rattlesnakes in the genera Crotalus and
Sistrurus (Viperidae), and anacondas in the genus Eunectes (Boidae),
are ovoviviparous and retain the eggs within their body until they are
almost ready to hatch [129]. e common boa Boa constrictor (Boidae)
and the green anaconda E. murinus are fully viviparous, nourishing
their young through a placenta as well as a yolk sac [130]. A few
snake species such as the eastern copperhead Agkistrodon contortrix
and the cottonmouth Agkistrodon piscivorus - both North American
snake species in the family Viperidae - can reproduce by facultative
parthenogenesis [131].
All snakes are carnivorous, eating small animals including lizards,
frogs, other snakes, small mammals, birds, eggs, sh, snails, worms,
and/or insects [21]. On the other hand, many snakes are prey for,
among others, centipedes, scorpions, weasels, ferrets, birds, and other
reptiles including other snakes [132]. For these reasons, snakes have
developed an elaborate arsenal of characteristic defenses including,
among others, defensive stances, hissing, threat displays, strike poses,
attacking, and biting (see, for instance, references [133,134]). Although
some snakes may bite, only a few families are venomous and they
primarily use their venom to kill and subdue prey and initiate digestion
rather than for self-defense. Examples of venomous snake families are
the Viperidae (among others, rattlesnakes, bushmasters, and pit vipers),
Atractaspididae (such as stiletto snakes and snake-eaters), Elapidae
(including, among others, Australian copperheads, sea snakes, coral
snakes, cobras, kraits, and mambas), and some Colubridae (such as tree
snakes, the boomslang Dispholidus typus, keelback snakes, and garter
snakes) [19].
Snakes produce their venom in their salivary glands which are
located in the back of their head. Venom is delivered by contracting
muscles in the head, exercising pressure on the venom glands [135].
More ‘advanced’ venomous snakes such as viperids and elapids inject
their venom through their hollow fangs in the upper jaw [79-81,135]
while rear-fanged snakes such as the boomslang have a groove on their
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teeth (also in the upper jaw) to channel venom into the wound [79-
81,135]. However, the Mozambique spitting cobra Naja mossambica
(Elapidae) spits its venom on an attacker [136]. And keelback snakes as
well as garter snakes do not produce their venom themselves: the former
sequester toxins from the poisonous toads they eat and secrete them
from nuchal glands [137], the latter use the neurotoxin tetrodotoxin
from the rough-skinned newt Taricha granulosa (Salamandridae) they
prey on [138].
Bioactive compounds from snakes: Snakes are symbols in many
religions and myths. In Christianity and Judaism, a serpent appears in
the rst book of the Bible when it tempts the rst couple, Adam and
Eve, with the forbidden fruit from the tree of knowledge of good and
evil [139]. Snakes also played prominent roles in ancient Egypt as a
decoration of the crown of the pharaohs, in the form of the primordial
snake god Nehebkau, and in the ritual suicide of Cleopatra [140]. In
Greek mythology, Medusa was one of the three Gorgon sisters who
had snakes for hair and whose gaze turned those who looked at her to
stone [141]. In ancient Greece, the serpent was also seen as the symbol
of medicine, presumably because of the association of the periodic
renewal of its skin with healing [142]. For this reason, Asclepius, the
Greek god of medicine, carried a serpent wound around his rod, a
symbol still used today to denote medicine [142]. Two other medical
symbols involving snakes are also still used today, namely the Caduceus
that stands for medicine in general, and the Bowl of Hygieia that
symbolizes pharmacy [142].
Snakes also have a long use in the traditional medical practices
of many cultures. In Mexico, rattlesnake pills made of dried ground
rattlesnake esh are indicated for curing a wide variety of ailments,
including impurities in the face, cancer, itching, rheumatism, varicose
veins, stress, heart disease, diabetes mellitus, hemorrhoids, and sexual
impotence [143]. However, ingestion of the pills has been associated
with salmonellosis [144]. In South African Zulu culture, traditional
healers are attired in python skin because pythons are associated with
power [145]. In many other traditional African cultures, the head of
a python is believed to reverse spells and bad luck, prevent potential
accidents from happening, and help attract a marital partner [146].
In many African societies python fat is topically applied to relieve
rheumatic pains [146], and in various Asian countries the blood from
live cobras is mixed with an alcoholic beverage and drunk to increase
sexual virility [147]. Well-known is the Japanese custom of leaving the
habu snake Protobothrops avoviridis (Viperidae) to steep in rice wine
or grain alcohol, turning it into habushu or habu sake [148].
Like those of helodermatid and varanid lizards [79-81], snake
venoms consist of complex mixtures of proteins and non-proteins with
a broad range of biological and pharmacological activities [149,150].
ese include, among others, enzymes such as secreted PLA2s, L-amino
acid oxidases (LAAOs), phosphodiesterases, acetylcholinesterases,
snake venom metalloproteinases (SVMP), and snake venom serine
proteases (SVSP), as well as non-enzymatic compounds such as
protease inhibitors, natriuretic peptides, 3FTXs, CRiSPs, Kunitz-type
inhibitors, and disintegrins [149,150]. ese compounds, either alone
or at certain combinations, elicit three broad types of pharmacological
eects, namely hemotoxicity, neurotoxicity, and cytotoxicity [150]. For
instance, certain PLA2s and 3FTX act on pre- or postsynaptic junctions
as antagonist of ion channels and nicotinic or muscarinic receptors,
causing paralysis and respiratory failure (see, for instance, reference
[151]), while other PLA2s and 3FTXs, along with SVMPs, cause local
tissue damage resulting in swelling, blistering, bruising, and necrosis,
and systemic eects such as hypovolemic shock (see, for instance,
reference [152]).
A myriad of drug development studies have explored the
pharmacological activities of the many bioactive compounds in snake
venoms [150]. is has resulted in the development of the above-
mentiond angiotensin-converting enzyme inhibitor captopril and its
derivatives from the venom of the Brazilian viper B. jararaca [17], as
well as various other important drugs. Eptibatide inhibits platelet
aggregation, reducing the risk of acute cardiac ischemic events, and
has been derived from a disintegrin in the venom of the rattlesnake
S. miliarius barbouri [97]. Tiroban also prevents the blood from
clotting and has been developed from the venom of the saw-scaled
viper Echis carinatus (Viperidae) [153]. Batroxobin is a thrombin-like
serine protease that cleaves brinogen, reducing brinogen levels, and
has been derived from the venom of the Brazilian Viperidae members
B. moojeni and B. atrox [154]. And the anti-ageing substance Syn-Ake®
that reduces the formation of wrinkles by relaxing the facial muscles,
is based on a synthetic tripeptide that has been developed on the
basis of the structure of waglerin 1 in the venom of the temple viper
Tropidolaemus wagleri (Viperidae) [155].
Antileishmanial compounds from snakes: Leishmaniasis is a
group of parasitic diseases caused by kinetoplastid agellates of the
genus Leishmania (Trypanosomatidae). ese parasites comprise two
subgenera, Leishmania and Viannia [156] which are found in both the
Old and the New World, and only in the New World, respectively [156].
e parasites are spread by female sand ies of the genera Phlebotomus
in the Old World and Lutzomyia in the New World [157] when they
draw a blood meal from an infected host (including a human being)
[157]. e Leishmania parasites exist as non-agellated amastigote
forms inside the host’s macrophages and as agellated promastigotes
in the gut of the sandy [157]. Twenty-one of the thirty known
Leishmania species are pathogenic to humans [157], and dependent
on the species they cause a broad spectrum of disease forms ranging
from cutaneous leishmanisasis and mucocutaneous leishmanisasis to
severe viscerotropic forms of leishmaniasis and post kala-azar dermal
leishmaniasis [158]. Cutaneous leishmaniasis is in some cases self-
limiting but may cause serious mutilation in other cases [158], while
visceral leishmaniasis - characterized by invasion of the parasites into
bone marrow, liver, and spleen - is invariably lethal if le untreated
[158].
e various forms of leishmaniasis are endemic in nearly hundred
countries throughout the world [159], particularly in poor populations,
disaster zones, and war-torn regions in tropical and subtropical parts of
the world [160], producing each year 0.7 to 1 million new cases [159].
Treatment is mainly with systemically given pentavalent antimonals
such as sodium stibogluconate and meglumine antimoniate;
amphotericin B and its analogues (particularly liposomal amphotericin
B); oral miltefosine; and/or paromomycin [158]. However, these drugs
cause serious side-eects, evoke resistance, are very costly and beyond
the reach of many endemic areas, require prolonged treatment, and/or
must be prepared and administered by complicated procedures [158].
ese considerations indicate an urgent need to develop novel, more
ecacious agents against the various forms of leishmaniasis.
Snake venoms and some of their ingredients displayed substantial
antiparasitic activities including activity against leishmaniasis [161].
For instance, the whole crude venoms of the Brazilian viper B.
jararaca and the Sonoran lyresnake Trimorphodon biscutatus lambda
(Colubridae), as well as those of the cascabel rattlesnake Crotalus
durissus terricus (Viperidae) (Figure 5) and the Marajó and Cerrado
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lancehead vipers Bothrops marajoensis and B. lutzi inhibited the growth
of promastigotes of L. (L.) major [162,163], and L. (L.) amazonensis
[164-166], respectively. Both leishmanial species are known to cause
cutaneous leishmaniasis [158]. e crude venoms of B. lutzi and B.
marajoensis, along with those from the horned desert viper Cerastes
cerastes (Viperidae) and the Egyptian cobra Naja haje (Elapidae), also
inhibited the growth of promastigotes of members of the L. donovani
complex [165-167], the causative agents of visceral leishmaniasis [158].
Various lines of evidence have implicated PLA2s, LAAOs, and
CriSPs in the antileishmanial activities of the venoms of these and other
snake species. e involvement of snake venom PLA2s in these eects
was supported by the substantial inhibitory actions of these compounds
on the growth, development, and infective capacity of promastigotes
and amastigotes from L. (L.) major [163], L. (L.) amazonensis, [168],
L. (L.) infantum [169], and L. (L.) amazonensis [170]. Importantly,
the antileishmanial eects have been associated with perturbation of
mitochondria, nuclei, and plasma membranes of the parasites [162,168]
as well as the release of cytotoxic cytokines from host neutrophils
against the parasites [170]. e latter observations were consistent
with the cytotoxic eects of a fraction of the venom from the Central
Asian cobra Naja naja oxiana (Elapidae) towards L. (L.) infantum
promastigotes and amastigotes following stimulation of the immune
system [171]. is venom also promoted the production of reactive
oxygen species and apoptotic-like mechanisms, and inhibited the
activity of arginase, a critical enzyme in the metabolism of Leishmania
parasites [171].
Support for antileishmanial activity of LAAOs came from the
notable inhibitory eects of LAAO-containing fractions from the
above-mentioned snake venoms on the growth of promastigotes
of L. (L.) amazonensis, L. (L.) infantum, L. (V. ) braziliensis, L. (L.)
donovani, and L. (L.) major [165,172-176]. Further fractionation of
the LAAO-containing fraction of the C. durissus terricus venom
yielded the proteins gyroxin, crotamine, and convulxin which also
elicited important activity against L. (L.) amazonenesis promastigates,
were not cytotoxic towards cultured J774 mouse BALB/c monocyte
macrophages, and displayed activity in a BALB/c mouse model of
leishmaniasis [164]. e antileishmanial eects of the LAAOs might be
attributed to their ability to provoke oxidative stress by forming oxygen
radicals and hydrogen peroxide [177,178].
An antileishmanial activity of a snake venom CRiSPs has so far
only been reported for the venom of the prairie rattlesnake Crotalus
viridis viridis (Viperidae) called crovirin [179]. is compound
displayed promising activity against L. (L.) amazonensis promastigotes
and amastigotes, and was only cytotoxic to normal mammalian cells
including peritoneal macrophages at considerably higher concentrations
than those required for its antileishmanial eect [179]. CRiSPs are
believed to mainly function as ion channel blockers [179,180], but
whether the antileishmanial activity of the C. viridis viridis CRiSP is
associated with such a mechanism is so far not known. Nevertherless,
together, these data support the potential of snake venoms as sources
for new classes of drugs against leishmaniasis.
Antiviral compounds from snakes: Pathogenic viruses have
plagued mankind since its existence and rst caused epidemics
when human beings settled in more densely populated agricultural
communities from the Neolithic period on, roughly 12,000 years ago
[181]. Under these conditions, viruses were able to rapidly spread and
become endemic [181]. Viruses having livestock (or domesticated
plants) as hosts also increased in frequency, and some evolved to
mutated versions that were able to infect humans [182]. Among the best
known examples of old and devastating viruses from zoonotic origin
are the smallpox viruses which have caused many massive pandemics
throughout human history [183], killing an estimated 300 million
people around the world in the twentieth century alone [184]. ese
viruses probably rst emerged in agricultural communities in India
about 11,000 years ago and probably descended from the poxviruses
of rodents [185].
Other viruses that have caused epidemics following the
establishment of large human communities were measles, mumps,
rubella, and polio, and they are believed to have emerged at the same
time as the smallpox viruses [182]. However, inuenza A viruses
are responsible for the most shattering epidemics in human history,
claiming 40 million to 50 million fatalities in the early twentieth
century as the ‘Spanish u’ [186]. e u pandemic returned in 1957
as ‘Asian u’ and then in 1968 as ‘Hong Kong u’ that killed about 3
million people [186]. Some of the inuenza viruses are believed to have
crossed the species barrier from ducks and waterfowl to pigs and from
there to humans [182].
Relatively recently emerging zoonotic viruses thought to
have emerged through one or more animal hosts are the human
immunodeciency virus (HIV), the Ebola viruses, and the severe
acute respiratory syndrome coronaviruses (SARS-CoVs) [187]. HIVs
are the causative agents of the acquired immunodeciency syndrome
(AIDS), Ebola viruses cause severe and oen fatal hemorrhagic fever,
and SARS-CoVs cause serious respiratory problems [187]. Despite its
virulence and rapid spread, SARS-CoV-1 did not cause the pandemic
that was feared [188]. However, SARS-Cov-2 that rst emerged in
Wuhan, China in November 2019, has rapidly spread around the world
and is responsible for the current pandemic with an enormous case-
fatality rate in particularly older people and those with pre-existing
comorbidities [188].
Today, many previously fatal viral diseases such as measles, mumps,
yellow fever, and poliomyelitis can be treated with vaccines [189], while
various others such as those causing herpes, AIDS, and hepatitis can
be kept in check with antiviral drugs directed at specic stages in the
viral life cycle [190]. However, there are still no vaccines or eective
therapeutics available for, among others, the dengue virus and the
Ebola virus, although these viruses pose massive public health threats
to tens of millions of people worldwide (see, for instance, references
[191,192]). Moreover, as illustrated by the 2009 inuenza pandemic
[193] and the present SARS-CoV-2 pandemic [188], more virulent
drug-resistant strains of viruses can rapidly develop and spread around
the world, necessitating continuous eorts to prevent and contain
outbreaks. ese considerations indicate an urgent need of more
ecacious antiviral treatments.
Various lines of evidence suggest that ingredients in snake venoms
may represent lead compounds of novel antiviral drugs [194,195]. Firstly,
the use of the venom of the black-necked spitting cobra Naja nigricollis
(Elapidae) (Figure 6) from sub-Saharan Africa as well as isolated
cytotoxins from the venom led to lysis of human erythrocytes infected
with the Sendai virus while leaving normal cells largely unaected
[196]. Furthermore, the crude venom of the cascabel rattlesnake C.
durissus terricus, as well as crotoxin, the main ingredient of the venom,
inhibited measles virus, dengue virus, and yellow fever virus infection
of cultured Vero African green monkey kidney cells [197,198] while
not aecting the viability of normal Vero cultures [197,198]. Crotoxin
has been found to consist of two components, crotapin and PLA2 [199],
both of which also displayed antiviral eects which added to each
other’s eect [197,198]. is was conrmed in subsequent studies using
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cultured Huh 7.5 human hepatocellular carcinoma cells infected with
the JFH-1 hepatitis C virus strain [200]: crotoxin was found to interfere
with the entry into as well as the release of virus particles from the host
cells, while crotapotin prevented the release of virus particles and PLA2
perturbed the entry and replication of the virus [200].
e antiviral activities seemed to be associated with interference
with the initial steps of the viral life cycle, i.e., the adsorption of virus
particles to the host cell’s plasma membrane and their penetration
into the cell [197,198]. Further studies showed that the activity of
PLA2 in the C. durissus terricus venom against the dengue virus
and other enveloped viruses may involve, in addition, the cleavage of
the glycerophospholipids in the viral lipid bilayer envelope, resulting
in partial exposure of the viral genomic RNA [201]. Support for the
importance of PLA2 in the antiviral eects of C. durissus terricus
venom has been provided by the phospholipase activity and virucidal
eects of recombinant PLA2 against the chikungunya virus, the dengue
virus, the yellow fever virus, and the Zika virus [202].
Snake venoms and some of their ingredients also elicited anti-HIV
activity. Several snake venom PLA2s protected human primary blood
leukocytes from infection by primary HIV-1 isolates, presumably by
interfering with the process of uncoating of virus particles, thus halting
the infection [203]. e PLA2 crotoxin in the venom of C. durissus
terricus showed in vitro activity against HIV that was probably
associated with the destabilization of cell-surface heparans which
are involved in the attachment of HIV to the plasma membrane of
host cells and their entry into the cells [204]. Furthermore, a LAAO
isolated from the venom of Stejneger's pit viper Trimeresurus stejnegeri
(Viperidae) inhibited HIV-1 infection of C8166 human T cell leukemia
in culture and replication of the virus in the cells at concentrations that
had little eect on the viability of the host cells [205]. Immunokine®,
an oxidized derivative of the α-toxin extracted from the venom of the
Indochinese spitting cobra Naja siamensis (Elapidae), inhibited the
infection of lymphocytes by HIV and feline immunodeciency virus
(FIV) by blocking the chemokine receptors CCR5 and CXCR4 [206].
Importantly, administration of a preparation with the trade name
Samayz® containing various components derived from snake venom
in conjunction with antiretroviral therapy to a patient with multidrug-
resistant HIV has reportedly led to a decreased viral load and an
elevated CD4+ cell count [207], providing additional support for the
anti-HIV activity of snake venom ingredients.
Testudines
Generalities about testudines: e order Testudines or Chelonii
consists of turtles, tortoises, and terrapins. Like other reptiles, these
animals are ectothermic, have scales covering their skin, breathe
through lungs, and lay eggs on land. However, unique to the Testudines
is the bony shell that encases their body [22, 208]. is characteristic
is captured in the names of this reptilian order which are based on the
classical Latin word ‘testudo’ for ‘tortoise’ and the ancient Greek word
‘khelone’ for ‘interlocking shields or armor’. Unlike the claws, nails,
horns, and beaks of other animals, the shells of testudines contain nerve
endings which respond to mechanical stimuli such as pressure and
vibration but also to those causing pain [208]. e testudines’ bony shell
is not an exoskeleton but a modication of the ribcage with elements
of the vertebral column, vertebrae, clavicles, and interclavicles, is not
shedded, and grows with the animals [22,208]. e dorsal part of the
shell is the carapace that can be tall and rounded, at, or some shape
in between, the ventral part is the plastron that covers most or part
of the bottom of the animals [208]. e carapace and the plastron are
connected to each other by a bony bridge or a exible ligament [208].
In many species, the shell is covered with scutes which are regularly
replaced by ecdysis [22,208], but in soshell turtles it is covered with
leathery or rubbery skin [22,208].
e distinction between turtles, tortoises, and terrapins is not based
on taxonomic criteria but on somewhat arbitrary and geographical
considerations. e term ‘turtle’ can be used to refer to all species of the
order Testudines including tortoises, but not all turtles are tortoises. is
is, because tortoises belong to the Testudinidae family that is a group
within the larger Testudines order. Furthermore, in the USA, ‘turtle’
refers to testudinians that are aquatic or semi-aquatic and ‘tortoise’
to terrestrial species, while in the United Kingdom freshwater species
are called ‘terrapins’ and salt water species are called ‘turtles’. And in
Australia, all turtles not residing in the ocean are named ‘tortoises’. In
this paper, ‘turtles’ refers to sea turtles that rarely leave the ocean (such as
the leatherback sea turtle Dermochelys-coriacea Figure 7), ‘tortoises’ to
turtles that spend most of their time on land (such as the giant tortoises
in the genus Chelonoidis (Testudinidae) from the Galápagos Islands),
and ‘terrapins’ to turtles that spend time both on land and in brackish,
swampy water (such as the North American common snapping turtle
Chelydra serpentina (Chelydridae)).
e Testudines are among the most ancient reptiles alive, with
only the tuataras considered more primitive [209]. e largest extant
testudian is the leatherback sea turtle D. coriacea that can attain a total
length of up to 3 meters and a weight of more than 900 kilograms
[210]. It is the fourth-heaviest modern reptile behind three species of
crocodilians [210]. Its carapace is covered by leathery skin and oily esh
and it is found in all tropical and subtropical oceans and even within the
Arctic Circle [210]. Some of the smallest testudines - an average carapace
length of 10 centimeters and a weight of slightly more than 100 grams
- are the speckled Cape tortoise Chersobius signatus (Testudinidae)
from the western part of South Africa [211], the attened musk turtle
Sternotherus depressus (Kinosternidae) that is endemic to southern
USA [212], and the bog turtle Glyptemys muhlenbergii (Emydidae)
from eastern USA [213].
e approximately 361 extant species of turtles, tortoises, and
terrapins are placed in 14 families and 97 genera [19]. Based on the
way they retract their head and neck within their shells, testudines are
grouped in two suborders, the Pleurodira and the Cryptodira [214].
e pleurodirans are also called side-necked turtles and fold their long
neck sideways to insert their head within the shell. e pleurodirans
Figure 4. The Komodo dragon Varanus komodoensis (Varanidae) (from: https://images.
app.goo.gl/eaLt1Hu9YMs4z2dN6)
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comprise 3 extant families including the Podocnemididae family of
South American river turtles [215]. e cryptodirans or hidden-necked
turtles lower their neck and pull their head straight back to conceal it
within their shell [216]. ey comprise the remaining 11 families and
include, among others, the highly migratory sea turtles in the families
Dermochelyidae and Cheloniidae [217].
Testudines heavily rely on scent to acquire food, obtain a mate,
nd appropriate nesting areas, recognize and localize predators, and
many of their other daily activities [218]. Some species can see color
in the range between near ultraviolet to red, and many probably have
exceptional night vision [218]. Most species can hear sound but are less
sensitive to high frequencies [218]. Testudines do not have teeth but
instead hard, at surfaces on their jaws that allow them to grip and tear
o bits of plants or animals for feeding [218]. Testudines display a wide
variety of mating behaviors but do not form pair-bonds or social groups
[219]. Most species bury their eggs in soil, sand, or rotting vegetation,
but some lay them on the ground in the open. Neither parent incubates
the eggs or attend them in any way; instead, the eggs are incubated by
environmental heat [219]. e young break free of the egg using an
egg tooth or caruncle aer 45 to 90 days of development and fend for
themselves aer hatching [219].
Testudines do not have fangs or venoms to defend themselves.
When threatened or under attack, many simply withdraw into their
shells. Species with reduced shells that do not oer sucient protection
make use of additional defensive tactics when confronted with danger.
For instance, musk turtles such as Sternotherus odoratus and mud turtles
such as Kinosternon subrubrum - both in the family Kinosternidae
- release a foul musky odor from two scent glands underneath their
carapace to deter predators [220]; Bell’s hinge-back tortoise Kinixys
belliana (Testudinidae) exudes a strong-smelling viscid material
from its cloaca when handled; and the radiated tortoise Astrochelys
radiata (Testudinidae) regurgitates its stomach contents when under
predator attack [221]. Although most turtles can bite, only a few use
biting as a defense. A few notable examples are the common snapping
turtle C. serpentine as well as the alligator snapping turtle Macrochelys
temminckii (Chelydridae) and the North American soshell turtles in
the genus Apalone (Trionychidae) [222].
Bioactive compounds from Testudines: e meat of turtles,
tortoises, and terrapins has long been considered a delicacy and is
included in exclusive soups and stews in, among others, Chinese,
Japanese, African, and Anglo-American cuisines, oen along with
the skin and the intestines. e species most commonly consumed
are the Chinese soshell turtle Pelodiscus sinensis (Trionychidae), the
Chinese three-striped box turtle Cuora trifasciata (Geoemydidae), the
Chinese big-headed turtle Platysternon megacephalum (Platysternidae),
the gopher tortoise G. polyphemus, and the common snapping turtle
C. serpentina. Dishes and beverages prepared with parts of testudians
are also consumed for their presumed health benets. In Chinese
culture, for instance, turtles are symbols of long life, personal wealth,
fertility, strength, and a happy household [223], and turtle ingredients
are believed to help maintain youthful beauty in females and improve
sexual performance in males [223,224]. Furthermore, in Chinese
traditional medicine, the shells and other parts of turtles and tortoises
are processed into tablets, powders, and ointments for treating a myriad
of conditions ranging from coughs and headache to a dicult childbirth
and cancer [225,226].
In western Africa, parts from sea turtles including the leatherback
D. coriacea are also believed to have healing properties and are used
to treat a variety of disorders including malaria, seizures, fever,
anemia, hepatitis, sexual underperformance, rickets in children, as
well as conditions caused by evil spirits [227,228]. And in several Latin
American and Caribbean countries, parts from turtles and tortoises
would treat a myriad of conditons ranging from respiratory complaints
and earache to rheumatism, diabetes mellitus, and cancer [229]. Some
of these products are even available in pre-packaged form or included
into cosmeceuticals. A few examples are the fat from the Amazon river
turtle Podocnemis expansa (Podocnemididae) and the green sea turtle
C. mydas that are marketed as crema de tortuga (turtle cream) [230] or
included into manufactured bathing soaps, lotions, skin care products,
anti-wrinkle formulations, and nail creams [231].
ese applications are supported by the results from pharmacological
studies indicating, among others, the high vitamin E content of the fat
from the green sea turtle C. mydas [230] and the presence of abundant
amounts of phenolic compounds and fatty acids with meaningful
antibacterial and antioxidant activities in the fat from the Amazon
river turtle P. expansa [232]. Notably, earlier studies [233] had provided
indications for the antiinammatory, antigargalesthetic (anti-itching
and anti-urticarian), and analgesic activities of turtle and tortoise oil,
and hinted on their potential usefulness in the prophylaxis and/or
treatment of cardiovascular diseases and psoriasis. So far, studies on the
pharmacological properties of parts of testudines and their potential
medicinal applicability are scant. Hereunder, the potential usefulness
of some of these preparations as immunomodulating compounds has
been addressed.
Cancer-immunomodulating compounds from testudines:
Immunomodulation involves therapeutic interventions aimed at
modifying the immune response in such a way that the ratio of the
dierent groups of immune cells are brought back into balance so that
the immune system can function correctly [234]. Immunomodulation
can involve either immunosuppression or immunostimulation.
Immunosuppression is useful to diminish the immune response against
transplanted organs in order to prevent rejection [235], and to treat
autoimmune diseases such as pemphigus, lupus, or allergies [236, 237].
Immunosuppression can be accomplished by interfering with antigen
presentation, T cell activation, or T cell proliferation [234] using,
among others, anti-CD 154 monoclonal antibodies, cyclosporine A,
rapamycin, or corticosteroids [238].
Figure 5. The cascabel rattlesnake Crotalus durissus terricus (Viperidae) (from: https://
images.app.goo.gl/dP4RjuPpKtpteCrG7)
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Immunostimulation is applied to augment the immune response
and restore healthy immune function in cases of, among others,
infectious diseases, primary or secondary immunodeciency, and
neoplastic disease [234]. Infectious diseases can be prevented by
vaccination, the most eective immunomodulatory technique [239].
Primary immune defects are oen manageable by allogeneic stem cell
transplantation [240], while secondary immunodeciencies caused
by, for instance, malnutrition or HIV, are most eectively managed by
treating the cause [241]. And immunomodulating therapies of cancer
attempt to improve the immune system’s ability to attack and eliminate
cancer cells using, among others, immune checkpoint inhibitors that
remove the inhibitory eects of immune checkpoint pathways, thereby
(re)activating cancer-targeting cytotoxic T cells; cytokines that regulate
immune cell maturation, growth, and responsiveness; agonists that
activate pathways for promoting T cell-mediated adaptive immune
responses; and adjuvants that help attack cancer cells by stimulating
general immune responses [242,243].
Preparations from testudines may also possess immunostimulatory
properties. For instance, administration of the blood plasma, a fraction
of the spleen extract, or an extract from the blood cells from the Russian
tortoise Agrionemys horseldii (Testudinidae) - considered one of the
most radioresistant animals [244] - to irradiated mice led to restoration
of the mice’s bone marrow cell populations and an increased survival
rate of the animals [245-248]. Numbers of peripheral blood leukocytes,
spleen colonies, and bone marrow mitoses, as well as RNA-synthetic
activity of irradiated bone marrow cells were also increased in animals
treated with the tortoise preparations [246,247]. Moreover, an aqueous
extract of the dried shell from the red-eared slider turtle Trachemys
scripta elegans (Emydidae) led to an increase in serum levels of IgG
as well as those of various lymphocyte populations in both normal
BALB/c mice and mice treated with the immunosuppressive agent
cyclophosphamide [249].
e immunomodulating substance in the spleen of the Russian
tortoise A. horseldii was identied as an oligopeptide with a molecular
weight up to 2,000 D that had been designated FTGN [244]. is
compound accelerated repopulation of irradiated bone marrow at
very low concentrations both in vivo and ex vivo, and a uorescence-
labeled derivative of FTGN selectively bound to CD34+ stem cells [244].
us, FTGN may play an important role in the proliferation of CD34+
cells and the repopulation of hematopoietic lineages aer irradiation
[244]. Interestingly, FTGN also protected the laboratory animals from
alopecia [244]. ese ndings suggest that parts from testudines may
contain an immunostimulating activity that may be useful in cancer
patients with bone marrow damage as a result of radiotherapy or
chemotherapy and in individuals undergoing autologous or allogenic
bone marrow transplantation.
Incidentally, orally administered powder from the meat of the
Chinese soshell turtle P. sinensis attenuated the increase in diameter
and weight of experimental solid tumors in a C3H/He mouse model
and prolonged the survival of the animals [250]. e powder did not
aect ascites tumors in the mice, suggesting that it did not directly kill
tumor cells and may act by activating the immune system [250]. Other
studies on the antitumor activity of testudines’ parts reported cytotoxic
eects of the extract from the shell of the Greek tortoise Testudo graeca
(Testudinidae) and of peptides isolated from enzymatic hydrolysates
of proteins from the Chinese three-striped box turtle C. trifasciata to
various animal and human carcinoma cell lines [251,252]. Furthermore,
peptides from the Chinese soshell turtle P. sinensis altered microRNA
expression in the AGS human gastric adenocarcinoma cell line
involving, among others, upregulation of several tumor suppressor
miRNAs [253].
Together, these observations suggest that testudines-
derived preparations may suppress cancerous growth through
immunomodulating as well as direct anticancer eects. is
supposition needs to be veried but if true, it supports the use of parts
from various so-shelled turtles in traditional Chinese medicine to
improve the prognosis of cancer patients undergoing radiotherapy and
chemotherapy [254].
Crocodilians
Generalities about crocodilians: e order Crocodylia comprises
a total of 26 recognized species [19] which are placed in three families,
namely the Crocodylidae (including the true crocodiles in the genus
Crocodylus), the Alligatoridae (including the genera Alligator and
Caiman), and the Gavialidae (that only consists of the gharial and the
false gharial) [19]. e three crocodilian families can be distinguished
from one another on the basis of the shape of the snout [56]. Gharials
have a long narrow snout with adult males developing a bulbous growth
at the tip called a ghara that is used to enhance vocal communication
[56]. Alligators and caimans have a broad snout in which the fourth
tooth of the lower jaw cannot be seen when the mouth is closed [56].
And Crocodylidae family members have various snout shapes but the
fourth tooth of the lower jaw is always visible when the mouth is closed
[56].
In addition to their long attened snouts, crocodilians are
characterized by their large, solidly built, lizard-like appearance. Hence
the name of this group of reptiles that is derived from the Ancient
Greek and Latin words ‘krokódeilos’ and ‘crocodilus’, respectively,
both meaning ‘small lizard’. ey have, furthermore, thick skin that is
covered with non-overlapping scales; laterally compressed tails; eyes,
ears, and nostrils at the top of the head, allowing them to stalk their
prey with most of their body underwater; conical, peg-like teeth for
eciently seizing and holding prey rather than mastication since they
swallow food unchewed; and massive, powerful jaw-closing muscles,
enabling the animals to exert an enormous bite force [56]. As in
birds, crocodilians have a four-chambered heart and a unidirectional
system of air ow around the lungs [56]. All crocodilians are excellent
swimmers and can also move well on land, although their limbs are
reduced in size [56]. Species living in locations without a shoreline even
climb trees to catch sunlight [255].
Crocodilians are mainly found in freshwater, saltwater, and brackish
habitats with relatively high temperatures where they spend most of
Figure 6. The black-necked spitting cobra Naja nigricollis (Elapidae) (from: https://
images.app.goo.gl/vkum2vsDp1MMoXMh7)
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their time in water. e main exceptions are the American alligator
Alligator mississippiensis (Alligatoridae) (Figure 8) [256] that inhabits
the more temperate south-eastern parts of the USA, and the Chinese
alligator Alligator sinensis (Alligatoridae) [257] that is encountered
in the relatively moderate areas around the Yangtze River in China.
e smallest living crocodilian is Cuvier’s dwarf caiman Paleosuchus
palpebrosus (Alligatoridae) that mainly inhabits ooded forests near
the major rivers and lakes in the central Amazon basin [258]. An adult
typically weighs 6 to 7 kg with males growing to an average length of 1.4
meters and females usually not exceeding 1.2 meters [258]. e largest
species of crocodylian in the world is the saltwater crocodile Crocodylus
porosus (Crocodylidae) from the saltwater habitats and brackish
wetlands throughout the tropical regions of Asia and the Pacic [259].
Females rarely surpass 3 meters, but males grow to a length of 4.6 to 5.2
meters and can weigh as much as 1,200 kilograms [259].
Crocodilians are typically solitary, although dominant males
usually monopolize reproductive females and patrol and defend
territories harboring the females [260]. Copulation occurs in the water
[260]. Females lay eggs in holes or in mounds and, unlike most other
non-avian reptiles, care for their hatched young [260]. e number of
eggs laid in a single clutch ranges from ten to y [260]. Crocodilian
eggs are protected by hard shells made of calcium carbonate [260].
e incubation period is two to three months [260]. e gender of the
hatchlings is determined by the temperature at which the eggs incubate:
constant nest temperatures above 32 °C produce more males, while
those below 31 °C produce more females [260].
Crocodilians are largely carnivorous, feeding on sh, crustaceans,
molluscs, birds, and mammals, although several species have also
been observed to consume fruit [261]. Some species like the Indian
gharial Gavialis gangeticus (Gavialidae) and the Australian freshwater
crocodile Crocodylus johnsoni (Crocodylidae) are specialized in feeding
on sh, insects, and crustaceans, while the Chinese alligator A. sinensis
and the South American broad-snouted caiman Caiman latirostris
(Alligatoridae) specializes in eating hard-shelled molluscs [261]. On the
other hand, the saltwater crocodile C. porosus and the American alligator
A. mississippiensis have generalized diets and opportunistically feed on
invertebrates, sh, amphibians, other reptiles, birds, and mammals
[261]. Conversely, crocodilians have a few predators and natural
enemies of their own [262]. Several birds of prey such as eagles and
many carnivorous mammals such as wild pigs hunt young crocodilians
[262]. Big cats such as lions, tigers, jaguars, and leopards sometimes
attack, kill, and eat adult caimans, crocodiles, and alligators [262]. Large
pythons may prey on crocodiles, territorial hippopotamuses regularly
kill large crocodiles, and elephants will not hesitate to attack crocodiles
on sight in order to protect their young [262]. Relatively small crocodile
species such as the Australian freshwater crocodile C. johnsoni are
even victims of larger and more dangerous species like the saltwater
crocodile C. porosus [262]. However, the most important defensive
mechanism of crocodilians that is believed to be at the basis of their
evolutionary success is their robust innate immune system.
Bioactive compounds from crocodilians: Similarly to those from
other reptiles [263], parts from crocodilians have a long use in various
forms of traditional medicine on dierent continents. Crocodile oil
extracted from the fatty tissues of the animals has been used for centuries
in the traditional medical systems of Ancient Egypt, China, and India
for treating a wide range of ailments including burns, alopecia, and
wounds; chest ailments and respiratory conditions; gastrointestinal
obstructions; rheumatism; high blood pressure; cancer, and as a vaginal
contraceptive solution [264-266]. Based on centuries-old information
from Amazonian Amerindian tribes [267], many Brazilians use the
fresh fat from the broad-snouted caiman C. latirostris, the black caiman
Melanosuchus niger (Alligatoridae), and Cuvier's dwarf caiman P.
palpebrosus to alleviate rheumatism [268-270]. e teeth from these
species are also worn as protection against snake bites [271]. Crocodile
oil is incorporated into cosmetics and personal care products due
to its anti-aging properties observed in human volunteers [272],
antimicrobial and antiinammatory activities in preclinical and clinical
studies [264], and woud-healing actions in laboratory rats [265].
More recent insights have revealed a unique asset of crocodilians
- although comparable to that mentioned above for monitor lizards
[86] - that makes them even more interesting for pharmacological
evaluations. is involves the apparent robust and resilient immune
system of these animals that enables them to thrive in heavily infested
aquatic environments [273], ght o life-threatening infections, and
rapidly recover from severe injuries with almost no symptoms of
microbial infections [274]. Indeed, even gaping wounds and missing
limbs sustained in battles with predators, prey, or conspecics do not
seem to seriously incapacitate crocodilians [274]. Furthermore, being
opportunistic feeders, many crocodilians scavenge dead and rotting
esh or other germ-infested foods, aggressively steal it from other
predators, or let their food deliberately decompose in order to be better
able to tear apart and digest the soened esh without falling ill [275].
Crocodilians are also capable of withstanding chronic exposure to
high concentrations of heavy metals such as arsenic, cadmium, cobalt,
chromium, mercury, nickel, lead, and selenium as well as high levels of
radiation, and still live for up to a 100 years without developing cancer
or other debilitating ailments [276,277]. ese observations and those
mentioned in the preceding alinea support that the immune system of
crocodilians is able to very eciciently deal with parasitic and microbial
infections as well as carcinogenic insults [278,279]. is quality may
represent a formidable evolutionary adaptation of these animals that
may explain why they were among the few survivors of the catastrophic
Cretaceous-Tertiary extinction event [277]. It may also explain why
they were able to thrive in the unsanitary, pest-infected habitats they
have lived in since their origin [280].
A number of thorough investigations have supported the presence
of antiparasitic, antimicrobial, antiviral, and anticancer entities in the
Figure 7. The leatherback sea turtle Dermochelys coriacea (Dermochelyidae) (from:
https://images.app.goo.gl/FwwZ4R88LnRnvSXPA)
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serum of crocodilians [281]. ese discoveries may pave the way for
a new generation of drugs against infectious diseases and cancer, and
are more comprehensively addressed hereunder. Of note, naturally-
occurring antibiotic compounds (in particular antibiotic peptides)
acting in host defense against infection are also present in other
organisms including bacteria, archaea, protists, fungi, plants, and
other animals [281,282] including monitor lizards [113-115]. ese
compounds elicited broad-spectrum activity against bacteria, yeasts,
fungi, viruses, and cancer cells [281,283]. ey display a net positive
charge of +2 to +9 due to the presence of positively charged amino
acids such as arginine, lysine, and histidine, and contain a high ratio
of nonpolar amino acids [283,284]. As a result, they are able to readily
bind to the negatively charged bacterial membranes [283,284], aer
which they insert into the cell membrane through their nonpolar part,
and are taken up into the cell [285].
Antimicrobial compounds from crocodilians: As mentioned
above, infectious diseases have been a major cause of morbidity and
mortality throughout human history [181]. ese diseases probably
became more common with the establishment of large human
settlements and the movement of people from rural to urban areas and
the domestication of animals [181]. In addition to the earlier mentioned
smallpox and u pandemics caused by pathogenic viruses [183,186],
these developments were accompanied by serious global and regional
outbreaks caused by pathogenic bacteria and parasites such as the
plague [286], cholera [287], tuberculosis [288], and syphilis [289], as
well as malaria [290], leishmaniasis [159,160], and intestinal infections
[291]. ese ailments were for centuries major causes of death until
they were replaced by non-communicable diseases from the second
half of the twentieth century on [292].
Despite the progress accomplished in recent decades, morbidity and
mortality due to infectious diseases is still very common. According to
estimates of the World Health Organization (WHO), there were in 2010
globally 300 to 500 million cases of malaria, 333 million cases of sexually
transmitted diseases, 33 million cases of HIV/AIDS, 14 million cases of
tuberculosis, and 3 to 5 million cases of cholera [293]. Furthermore,
every third death in the world was attributable to an infectious disease,
most notably a lower respiratory infection (3.46 million), a diarrheal
disease (2.46 million), HIV/AIDS (1.78 million), tuberculosis (1.34),
malaria (1.1 million), or measles (900,000) [293]. us, despite the broad
armamentarium of currently available antiparasitic, antimicrobial, and
antiviral compounds [294], these developments indicate a need of novel
forms of treatment of infectious diseases.
One way to go forward may involve the exploration of the
antimicrobial peptides in the serum of crocodilians. Particularly the
serum of the American alligator A. mississippiensis and the Siamese
crocodile Crocodylus siamensis (Crocodylidae) have been investigated
for the presence of these compounds. In both cases, crude fresh and
freeze-dried serum as well as partially puried serum samples were
found to be cytotoxic against a broad variety of bacterial strains as
well as clinical isolates of several pathogenic bacteria [295-301]. e
crude sera also inhibited the growth of various fungal species [296,298]
but did not aect the viability of the murine macrophage-like cell line
RAW 264.7 [300]. In addition, the A. mississippiensis serum elicited
activity against HIV-1, West Nile virus, and Herpes simplex virus type
1 [296,302].
Partial purication of the crude sera led to the identication of
several low-molecular-weight, hydrophobic, and cationic peptides
with antibacterial activity - including activity against multidrug-
resistant strains [301] - that were able to perturb and damage bacterial
membranes and penetrate into the cytoplasmic space [295,296,299-
301,303,304]. And using microparticles to harvest cationic peptides
from biological samples followed by the de novo sequencing of the
captured peptides, forty-ve potential antimicrobial peptides were
identied from the plasma of A. mississippiensis [305]. Eight of these
peptides were chemically synthesized and were active against various
bacterial strains [305]. Furthermore, both the peptides leucrocin I–IV
isolated from C. siamensis white blood cells and the synthetic leucrocin
I derivative NY15 inhibited the growth of various bacterial reference
strains and clinical isolates, targeted bacterial plasma membranes, and
were non-toxic to mammalian cells at bacteriolytic concentrations
[306,307]. And a peptide obtained by hydrolysis of C. siamensis
hemoglobin exerted bactericidal activity against E. coli, S. aureus, as
well as K. pneumoniae and P. aeruginosa via a mechanism that might
involve iron dysregulation and oxidative stress [308].
e antibacterial eects of crocodilian antimicrobial peptides
may be mediated, at least partly, by antioxidant and antiinammatory
activities [309-312]. ese activities have been associated with the
hemoglobin fraction, hemoglobin hydrolysates, crude leukocyte
extract, and plasma from the animals [309,311,312]. us, the immune
system of crocodilians seems to contain protective molecules that may
serve as lead compounds for a new generation of antibiotics. One of
the rst medications emerging from this concept was an anti-acne gel
containing crude C. siamensis leukocyte extract [313] that displayed
considerable in vitro antibacterial activity against Propionibacterium
acnes and substantial inhibitory eects on proinammatory markers
and signs of inammation in infected mouse ears [313].
Anticancer compounds from crocodilians: Cancer refers to a
group of over 200 distinct disease forms that can start in almost any
organ or tissue of the body, and is characterized by the uncontrolled
growth of abnormal cells, their invasion into adjacent tissues, and their
spread to distant organs via blood and lymph vessels [314]. e latter
process, metastasis, is a major cause of death from cancer [314]. e
biological events at the basis of cancer are aberrations in oncogenes,
tumor suppressor genes, and/or repair genes [314] which lead to
the transformation of normal cells to a precancerous lesion and the
subsequent progression to a malignant tumor in a multistage process
[314]. ese changes are the result of biological or internal factors such
as older age, being male or female, and/or inherited genetic defects;
environmental and/or occupational exposures to, among others,
carcinogenic chemicals, radioactive materials, radon, UV radiation,
ne particulate matter, and/or asbestos; as well as lifestyle-related
factors such as inappropriate dietary habits, lack of physical activity,
and the use of tobacco and/or alcohol [315].
According to estimates of the International Agency for Research
on Cancer, there were an estimated 19.3 million new cancer cases and
almost 10.0 million cancer deaths in 2020 [316]. e most commonly
diagnosed cancers were female breast cancer (11.7%), lung cancer
(11.4%), colorectal cancer (10.0%), prostate cancer (7.3%), and stomach
cancer (5.6%), and the leading causes of cancer death were lung cancer
(18%), colorectal cancer (9.4%), liver cancer (8.3%), stomach cancer
(7.7%), and female breast cancer (6.9%) [316]. Notably, cancer was
in 2019 the rst or second leading cause of death before the age of 70
years in 112 of 183 countries throughout the world and ranked third
or fourth in a further twenty-three countries [317]. e therapeutic
modalities for treating cancer include surgery, radiation therapy,
chemotherapy, immunotherapy, targeted therapy using small-molecule
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J Transl Sci, 2021 doi: 10.15761/JTS.1000457 Volume 7: 15-23
drugs or monoclonal antibodies, and/or hormonal therapy [318].
Nevertheless, most cancers remain fatal, particularly when detected at
an advanced stage [314]. is implies a need for more ecacious forms
of treatment of neoplastic disease. Many eorts are being dedicated to
this goal, including improved early diagnosis, better supportive care, the
development of highly specic targeted therapies, and the identication
of novel, more ecacious antineoplastic compounds.
As mentioned before, crocodilians can survive up to 100 years
without developing cancer while being regularly exposed to well-
known cancer-causing compounds [276,279]. Various lines of evidence
support that their immune system is able to very eciciently deal with
carcinogenic insults in addition to microbial and parasitic infections.
Firstly, extracts of C. siamensis leukocytes [319,320], a fraction of C.
siamensis bile called ESC-3 [321], as well as serum and heart lysates,
a gall bladder lysate, and the bile of the mugger crocodile C. palustris
(Crocodylidae) [322] inhibited the proliferation of various tumor cell
lines in culture. e C. siamensis leukocyte extract did not aect the
viability of non-cancerous cells [320] but stimulated the overproduction
of reactive oxygen species in cancer cells [320] and inhibited the
formation of colonies as well as the migration and invasion of these
cells [319,320]. e latter observation might be attributed to a decrease
in the activities and levels of matrix metalloproteinase-2 and -9 [319]
following the disruption of signaling via vascular-endothelial growth
factor- and integrin-mediated pathways [319].
Notably, the C. siamensis leukocyte extract and the ESC-3 bile
fraction stimulated the expression of pro-apoptotic proteins such as
caspase-3, caspase-8, p53, and XIAP, and inhibited that of apoptosis-
regulating proteins such as Bcl-2, causing the cancer cells to undergo
apoptosis through the mitochondria-dependent pathway [319-
321]. Further investigations revealed that the anticancer activities
in crocodilian preparations were attributable to the same peptides
involved in their antimicrobial activities. For instance, the KT2, RT2,
and RP9 peptides derived from the crude C. siamensis leukocyte extract
were cytotoxic against various tumor cell lines and killed these cells by
apoptosis [323,324] while not aecting the viability of non-cancerous
cell lines [324]. e cytotoxic eects might be attributed to interference
with intracellular signaling pathways involved in the regulation of
the cell cycle [324,325], and the resulting apoptosis might also be
associated with a decreased expression of pro-apoptotic genes and an
increased expression of tumor suppressor genes [324]. ese changes in
expression and levels of apoptosis-promoting and apoptosis-countering
proteins were also observed in HCT116 human colon cancer xenogras
in BALB/c nude mice treated with the RT2 or the KT2 peptide, in
addition to a decrease in volume and weight of the xenogras [326,
327].
Parallel cell cuture studies showed that the RT2 and the KT2
peptides interacted with the cancer cell’s plasma membrane, were
internalized by endocytosis, and caused nuclear condensation and clear
signs of apoptosis, supporting that they exerted their cancer cell killing
eects in a comparable manner as their antimicrobial eects [328].
It thus seems that the cancer-ghting activities of crocodilians are
associated with the antimicrobial peptides that are part of their innate
immune system [276,279,329]. ese (positively charged) anticancer
peptides presumably exert their cancer cell-killing actions by the same
molecular principles as their antimicrobial eects, namely perturbation
of the cancer cells’ plasma membranes through electrostatic interactions
[329]. is is, because cancer cell membranes generally overexpress
anionic molecules, exhibiting a net negative charge [330] that is similar
to that of bacterial cells [331]. As a result, the anticancer peptides
selectively perturb cancer cell membranes while leaving those of
healthy mammalian cells unaected [330], resulting in either apoptosis
through the mitochondrial lytic system, or necrosis via cell membrane
lysis [332]. Further research in these crocodilian compounds may open
the door to novel modalities for treating cancer.
Concluding remarks
Similarly to those from many invertebrates [333-335] and
amphibians [336], the exploration of bioactive compounds from
reptiles may yield structurally novel and mechanistically unique
lead compounds for developing breakthrough medicines. is paper
has lied a corner of the veil, reviewing the opportunities for the
development of anticoagulants and antiplatelet drugs as well as wound
healing-promoting, antileishmanial, antiviral, immunomodulating
antimicrobial, and anticancer compounds from various species, genera,
or families of reptiles. e ACE inhibitors captopril and its analogues,
the GLP-1 agonist exenatide, and the platelet inhibitor eptibatide are
living proof of these opportunities [17,18,97].
So far, only a fraction of the complex venomous mixtures and the
resilient immune system from a relative handful of reptiles has been
investigated. is suggests that this animal class represents a considerable
and so far largely untapped source of novel therapeutics. Indeed, the
venoms of helodermatid lizards may yield second generation GLP-1
agonists against type 2 diabetes mellitus [337] and novel treatments for
Alzheimer’s disease [338]. e hemotoxic, neurotoxic, and cytotoxic
compounds in the venoms of snakes [150] may produce promising
lead compounds for treating a variety of human ailments in addition
to thrombotic disorders [150,195]. Further exploration of the biology
of varanids, testudines, and crocodilians may produce surprising
results that open new avenues for further exploration. For instance,
the conditioned media of bacteria from the gut of the Amboina box
turtle Cuora amboinensis (Geoemydidae) exerted potent and broad
antibacterial activity including activity against methicillin-resistant
Staphylococcus aureus while not aecting the viability of human cells
[339], suggesting another clinical application of a reptile species.
An important condition for these previsions to become reality
is meticulous conservation of this class of animals. However, habitat
Figure 8. American alligator Alligator mississippiensis (Alligatoridae) (from: https://
images.app.goo.gl/AAhg2HhNoVT7uEZZ9)
Mans DRA (2021) Exploring the global animal biodiversity in the search for new drugs - Reptiles
J Transl Sci, 2021 doi: 10.15761/JTS.1000457 Volume 7: 16-23
destruction, pollution, climate change (many turtles have environmental
sex determination), and introduced invasive species result in enormous
biodiversity loss including reptiles [340].
Also, the growing demand for reptiles throughout the world
maintains the unsustainable overexploitation of many reptilian species
for food, pets, leather, as well as traditional and ritual purposes, which
further contributes to the decline of this class of animals [263,341-
343]. In fact, at this moment, the International Union for Conservation
of Nature and Natural Resources (IUCN) has classied 332 reptilian
species as critically endangered, 588 as endangered, and 538 as
vulnerable [344].
For these reasons, the impact on the biodiversity loss due to human
causes (habitat destruction, pollution, and climate change) must be
controlled through proper national legislation, enforced controls, as
well as cultural shis in public attitudes towards the environment.
Obviously, procedures against the release of invasive non-native species
that can be harmful to reptile populations must also be prohibited.
Furthermore, international agreements must be made to restrict the
trade in vulnerable and endangered reptile species, and threatened
species must be saved from imminent extinction by expanding
populations in ex situ captive breeding programs and reintroducing
them in the wild following proper habitat protection, changes in cultural
attitudes, and strengthened international trade regulations. Hopefully,
these steps can avert the alarming decline in reptile populations and the
loss of a potentially valuable source of lead compounds for innovative
therapeutics.
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