Analgesic action
|
Conotoxins and spider toxins that block voltage-sensitive calcium chanels are potent analgesics
Neurotoxin Tx3-6 from brazilian armed spider
displayed higher efficacy and long-lasting analgesia in a thermal model of pain,
when compared with omega-conotoxin MVIIA. Tx3-6 was also more effective to reverse previously
installed persistent chemical and neuropathic pain. It is suggested that Tx3-6 might be useful
in the control of persistent pathological pain
[Souza et al., 2008].
The tarantula spider toxin GsMTx4
was shown to reduce mechanical and neuropathic pain . However, GsMTx4 did not
affect response to thermal stimuli
[Park et al., 2008].
Omega-conotoxin MVIIA (Ziconotide) is a potent
analgesic and has been approved for the treatment of severe chronic pain
[Wallace 2006].
|
Anthelmintic activity
|
Cyclotides possess anthelmintic activity
- Several Kalata and cycloviolacin
peptides were shown to display significant activity in inhibiting larvae development and adult motility
of Haemonchus contortus and Trichostrongylus colubriformis larvae, two important gastrointestinal
nematode parasites of sheep.
The activity displays no chiral selectivity and appears to be related to clustered basic residues
suggesting that membrane interaction rather than interaction with a receptor is involved in the
cyclotide anthelmintic activity
[Colgrave et al., 2008].
|
Anti Erectile Dysfunction (ED)
|
A spider toxin induces penile erection in rats
- The spider toxin Tx2-6 was shown to induce
and facilitate the ganglionic-stimulated penile erection in rats. It also displayed a potentiation
effect on penile erection of animals presenting severe erectile dysfunction such as the
deoxycorticosterone-acetate-salt hypertensive rats. The potentiating effect of Tx2-6 on erection seems
to be mediated by relaxation of the vasculature and smooth muscle in the corpus cavernosum induced by
the release of NO
[Nunes et al., 2008].
- Also note that the agouti-related and the agouti-signaling
proteins act on the melanocortin system that is involved in sexual function.
|
Antimalarial activity
|
Toxins from the venom of the tarantula Psalmopoeus cambridgei display strong antiplasmodial activity
|
Antimicrobials
|
Several knottins display antimicrobial activities
• A review about antimicrobial activity of plant peptides, including some knottins
[ Tam et al., 2015 ]
• In Bemisia tabaci, three knottin-like antimicrobial peptide genes are activated in response to the pathogen Pseudomonas aeruginosa
[ Zhang et al., 2014 ]
|
|
Source |
Knottin |
PDB ID |
Inhibits growth of |
|
|
|
gram + |
gram - |
fungi |
Plant |
PAFPS |
1DKC |
|
|
+ |
Plant |
Kalata B1 |
1KAL
1K48
1NB1
|
+ |
|
|
Plant |
Circulin A |
1BH4 |
+ |
|
|
Plant |
Circulin B |
|
+ |
+ |
|
Plant |
Cyclopsychotride |
|
+ |
+ |
+ |
|
|
|
|
|
|
Crab |
Tachystatin |
1CIX |
+ |
+ |
+ |
Antitumors
|
Antitumor activities have
been shown for PCI and cyclotides
- The Potato Carboxypeptidase inhibitor
PCI is an antagonist of
human EGF and inhibits tumor cell growth
[Blanco-Aparicio et al., 1998
]
- The cyclotides varv A, varv F,
and cycloviolacin O2 display
cytotoxicity for several human tumor cell lines [Lindholm
et al., 2002]. The activity profiles
differed significantly from those of antitumor drugs in clinical
use, suggesting a new mode of action for these cyclotides.
- Cycloviolacin O2 Disrupts Lipid Membranes.
Cytotoxic, antimicrobial, hemolytic,
and insecticidal effects are likely all connected to membrane disruption.
[Svangard et al., 2007
].
|
Protease inhibitors
|
The first known Knottins
were protease inhibitors
Inhibitors with the knottin scaffold have been isolated from plants.
Insects and phytopathogenic microorganisms secrete enzymes causing
proteolytic digestion or proteins. It is likely that, to defend themselves
from these attacks,
plants have developped expression of proteinase inhibitors.
[Habib & Fazili, 2007]
- Cyclotide psysol 2:
inhibitor of human prolyl oligopeptidase (POP)
[Hellinger et al., 2015].
- Roseltide:
a knottin-type neutrophil elastase inhibitor derived from Hibiscus sabdariffa
[Loo et al., 2016].
- PCI: The potato
carboxypeptidase A inhibitor PCI inhibits its cognate enzyme
through its C-terminus [Rees
& Lipscomb, 1982].
- Squash:
The serine protease inhibitors of the "squash"
family inhibit their cognate enzyme through a canonical loop
located between Cys1 and Cys2 [Bode
et al., 1989].
- α-Amylase:
The α-amylase inhibitor from Amaranth AAI, inhibits α-amylase
from insects using a new mode of action. The interaction surface
includes two segments: (i) the loop between Cys1 and Cys2 and
(ii) the last strand of the β-hairpin [Pereira
et al., 1999].
|
Toxins
|
Toxic knottins inhibit ion channels, but
the mechanism of inhibition remains unknown.
It has been shown that the spider toxin VSTX1 reaches its target
by partitioning into the lipid membrane
[Lee & MacKinnon, 2004].
Moreover, both the spider toxin GsMTx4, and its enantiomer, enGsMTx4,
were shown to modify the gating of the target ion channel, ruling out the
traditional lock-and-key model of ligand-protein interactions. It is hypothesized
that GsMTx4 and enGsMTx4 alter the lipid packing at the bilayer/solution/channel
interface [Suchyna et al., 2004;
Garcia, 2004]. Molecular dynamics
simulations have evidenced two modes of binding between GsMTx4 and membranes. A
deep binding is favored when a DPPC (dipalmitoyl-phosphatidylcholine) membrane is
used at 310 K, indicating that toxin binding with biological membranes is affected
by the structure of the lipid acyl chains
[Nishizawa & Nishizawa, 2007].
Further studies have shown however that bilayer partitioning is not a universal
property of the toxic knottins that interact with ion channels
[Posokhov et al., 2007].
More recently, the asteropsin A, an unusual cystine-crosslinked peptide from porifera, has been shown to induce neuronal Ca2+ influx when it was administered together with the Na+ channel activator veratridine
[Li et al., 2013].
In 2016, a sodium channel inhibitor ISTX-I with a novel structure has been discovered and provides a new hint at the evolutionary link between two toxin folds
[Rong et al., 2016].
Toxic Knottins are able to
block many ion channels
exemples are shown below |
Channel |
Knottin |
PDB ID |
Sodium channel agonist/antagonist |
delta-conotoxin TXVIA |
1FU3 |
mu1 sodium channel receptor |
conotoxin EVIA |
1G1Z |
Potassium channel blocker |
kappa-conotoxin PVIIA |
1AV3
1KCP |
kv4-2 Potassium channel blocker |
Heteropodatoxin-2 |
1EMX |
Potassium channel gating modifier |
Hanatoxin-1 |
1D1H |
Calcium channel blocker |
omega-conotoxin GVIA
omega-atracotoxin HV2A |
2CCO
1G9P |
N-type calcium channel blocker |
omega-conotoxin MVIIA |
1MVJ
1MVI
1DW4
1I26 |
L-type calcium channel blocker |
omega-conotoxin TXVII |
1F3K |
Calcium channel gating modifier |
omega-grammotoxin SIA |
1KOZ |
Sodium channel inhibitor |
Neurotoxin ISTX-I |
2NDI |
Sodium channel inhibitor |
Conotoxin mu O-GVIIJ |
2N8H |
|
|
|
Insecticids
|
Few Knottins have shown insecticidal
activity
- Orally active insecticidal peptide (OAIP-1) (PDB ID: 2LL1)
from venom of the Australian tarantula Selenotypus plumipes [Hardy et al., 2013].
- J-Atracotoxin-HV1C (PDB ID: 1DL0)
- Kalata B1 and other cyclotides display insecticidal activities.
It has been shown that the insecticidal and hemolytic activity of kalata B1 are both dependent on a cluster
of hydrophilic residues separate from the membrane binding face. It is postulated that specific self-association,
in combination with membrane binding mediates cyclotide bioactivities
[Simonsen et al., 2008]. Kalata B1 has been shown to disrupt
epithelial cells in the midgut of lepidopteran larvae and consequently to negatively affect nutrient uptake
[Barbeta et al., 2008].
- α-Amylase inhibitor AAI
(PDB ID: 1CLV)
- Plant proteinase inhibitors:
Leaf-specific over-expression of the potato inhibitor PI-II and of the knottin PCI (carboxypeptidase
inhibitor) results in increased resistance to Heliothis obsoleta and Liriomyza trifolii
larvae in homozygote tomato lines expressing high levels of the transgenes
[Abdeen et al., 2005].
|
Others
|
Besides above activities,
it is worth noting that
- Knottin-1 gene of whitefly
[ Hariton Shalev
et al., 2016] displays antiviral activity on tomato yellow leaf curl virus.
- Circulin A, cycloviolins A-D and kalata B8
[ Hallock
et al., 2000; Daly
et al., 2006] displays anti-HIV activity.
- Cyclopsychotride A inhibits neurotensin
binding to HT-29 cell membranes.
- Cycloviolacin H4
displays the highest hemolytic activity among
cyclotides. It has been proposed that this activity correlates with the size of a
surface-exposed hydrophobic patch [
Chen et al., 2006].
- Kalata B1
is used in traditional medicine
for its uterotonic activity
- Agouti and
Agouti-related proteins (AgRP) are endogeneous antagonists of
the melanocortin receptors (MCRs) [Gantz and Fung, 2003;
Stutz et al., 2005;
Pritchard et al., 2005].
The normal role of agouti in mammals is to determine coat
color in conjunction with MC1R and the melanocortin peptide α-melanocyte-stimulating hormone
(α-MSH).
Hence the term agouti that refers to a hair color pattern characterized by subapical yellow bands.
Interestingly, agouti also acts as an antagonist of hypothalamic α-MSH, a major satiety factor,
and is thus involved in obesity.
Studies in humans revealed associations of AGRP single nucleotide polymorphisms
with resistance to obesity.
Administration or overexpression of AgRP increases intake of fat diet
On the other hand, absence or reduced functionality of AgRP leads to an increased lifespan
[Ilnytska & G. Argyropoulos, 2008;
Tracy et al., 2008].
As the melanocortin system is involved in diverse physiological functions, including pigmentation,
energy homeostasis, inflammation, fat intake and sexual function. Melanocortin-based drugs are therefore considered
for the treatment of skin cancer, obesity, erectile dysfunction, inflammatory diseases, pain, etc.
|
|