Abstract
Background and purpose: intrinsic Xase (iXase) is the final and
rate-limiting enzyme complex in the intrinsic coagulation pathway, which
may be the target for anticoagulation and anti-thrombosis with lower
bleeding tendency. A depolymerized fucosylated glycosaminoglycan (dHG-5)
with molecular weight of 5.2 kDa was prepared from sea cucumber
Holothuria fuscopunctata, showed promising druggability as an
anticoagulant targeting iXase. Like heparin, the drug candidate dHG-5 is
composed of a series of oligosaccharides. Therefore, it is necessary to
clarify these oligosaccharides’ structures and contents in dHG-5, and
their contribution to the pharmacological activities of dHG-5.
Experimental approach: These oligosaccharides’ structures were confirmed
by 2D NMR and MS spectra. The coagulation factor inhibition and factor
IXa-binding activities were analyzed by chromogenic substrates and BLI,
respectively. Anticoagulation was evaluated by clotting time.
Antithrombotic activity and bleeding risk were evaluated by deep venous
thrombosis model and tail-bleeding model, respectively. Key results: Our
data revealed that 1) the nine purified oligosaccharide components were
homologous and shared the common formula, which accounted for about 95%
of dHG-5, 2) the relationships of anti-iXase, f.IXa-binding,
APTT-prolonging and antithrombotic activity potenies (y) and
oligosaccharides’ molecular weight (x) fitted well with power function
(y = a × x b), 3) the activity potencies of dHG-5 were approximately
equivalent to the weighted average sum of those of its oligosaccharides,
4) dHG-5 showed antithrombotic activity with low bleeding tendency and
predictable pharmacodynamics characteristic. Conclusion and
Implications: dHG-5 has antithrombosis with low bleeding tendency, and
clear chemical composition and pharmacological properties, which makes a
good preparation for the clinical study.