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Anticoagulant CLPs bind the Gla domain of clotting factor IX and/or X in
Figure 4: Structures of Dimeric and Multimeric C-type
the presence of Ca
2+
.
58
Other targets of CLPs are platelet GPIb and/or
Lectin-like Proteins
GPVI or vWF. The GPIb-binding CLPs can cause either platelet
agglutination or inhibition in vitro depending on the stoichiometry of A B
bindings.
59
However, the affinity of binding is probably lower than vWF,
α
resulting in competitive inhibition in vivo. Some CLPs are disulphide-linked
higher multimers and bind GPVI, with or without GPIb-activating signal Domain Binding
transduction in platelets. Higher multimer has been implicated in receptor
swap site
clustering and, thus, activation.
16
Examples are alboaggregin A (α
1
α
2
β
1
β
2
)
β
and alboluxin ((αβ)
3
), which activate GPVI and GPIb,
60,61
while convulxin
(αβ)
4
bind GPVI and GPIa/IIa, another collagen receptor. In contrast,
stejnulxin
62
and trowaglerix can activate only GPVI, whereby trowaglerix
A: Dimeric; B: Multimeric.
also causes subsequent GPVI shedding and later platelet inhibition.
63
Furthermore, dimeric botrocetin and bitiscetin target vWF and/or GPIb, prothrombinase complex.
67
PLA
2
that binds vascular endothelial growth
enhancing their interaction.
64
Finally, bothrojaracin, the (pro)thrombin factor (VEGF) receptor, promoting angiogenesis, has been reported.
68
exosite binder, demonstrates a novel mechanism of anticoagulation.
Perspectives
Platelet-targeting CLPs are used to dissect the mechanisms of platelet Snake-venom proteins are proven useful tools for diagnosis and
activation mediated by each GP receptor. In addition, bothrojaracin investigation as they affect almost all aspects of the haemostatic
could treat a rat model of thrombosis.
65
system. However, therapeutic applications of venom derivatives are
limited by potential immunogenicity and the parenteral route of
Phospholipases A2 administration, making them unsuitable for repeated treatments. In
The enzymes originating from extracellular phospholipase A2 (PLA
2
) are addition, they have to compete with a lot of efficient and safe
animal enzymes that help gastrointestinal digestion and mediate antithrombotics and anticancer treatments on the market or in
inflammatory and antimicrobial activities.
66
The anticoagulant development. Identification of diseases or patient subgroups without
properties have been reported in snake venom PLA
2
and are effective remedies, employment of venom components to study
independent of phospholipase activity. The mechanism is likely to be pathogenesis and, then, production of small molecular mimetics as
direct binding, hence inhibiting the activated clotting factor Xa or treatments may be the way of drug discovery in the future. ■
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10 EUROPEAN HAEMATOLOGY
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