Design and Structure−Activity Relationships of Potent and Selective Inhibitors of Blood Coagulation Factor Xa

The saliva of blood-sucking leeches contains a plethora of anticoagulant substances. One of these compounds derived from Haementeria ghilianii, the 66mer three-disulfide-bonded peptide tridegin, specifically inhibits the blood coagulation factor FXIIIa. Tridegin represents a potential tool for antithrombotic and thrombolytic therapy. We recently synthesized two-disulfide-bonded tridegin variants, which retained their inhibitory potential. For further lead optimization, however, structure information is required. We thus analyzed the structure of a two-disulfide-bonded tridegin isomer by solution 2D NMR spectroscopy in a combinatory approach with subsequent MD simulations. The isomer was studied using two fragments, i.e., the disulfide-bonded N-terminal (Lys1–Cys37) and the flexible C-terminal part (Arg38–Glu66), which allowed for a simplified, label-free NMR-structure elucidation of the 66mer peptide. The structural information was subsequently used in molecular modeling and docking studies to provide insights into the structure–activity relationships. The present study will prospectively support the development of anticoagulant-therapy-relevant compounds targeting FXIIIa.

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Reaction pathway for inhibition of blood coagulation factor Xa by tick anticoagulant peptide

Biochemistry ◽

10.1021/bi00138a019 ◽

1992 ◽

Vol 31 (23) ◽

pp. 5374-5380 ◽

Cited By ~ 41

Author(s):

Susan P. Jordan ◽

Shi Shan Mao ◽

Sidney D. Lewis ◽

Jules A. Shafer

Keyword(s):

Blood Coagulation ◽

Reaction Pathway ◽

Factor Xa ◽

Coagulation Factor ◽

Tick Anticoagulant Peptide

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Two parallel prothrombin activator systems in Australian rough-scaled snake, Tropidechis carinatus

Thrombosis and Haemostasis ◽

10.1160/th04-07-0435 ◽

2005 ◽

Vol 93 (01) ◽

pp. 40-47 ◽

Cited By ~ 14

Author(s):

Md. Abu Reza ◽

Sanjay Swarup ◽

Manjunatha Kini

Keyword(s):

Blood Coagulation ◽

Blood Clotting ◽

Cdna Sequence ◽

Factor Xa ◽

Coagulation Factor ◽

Venom Gland ◽

Factor X ◽

Specific Expression ◽

Life Saving ◽

Sequence Encoding

SummaryIt is uncommon for similar pathways/systems to be involved in highly divergent functions within single organisms. Earlier, we have shown that trocarin D, a venom prothrombin activator, from the Australian rough-scaled snake Tropidechis carinatus, is structurally and functionally similar to the blood coagulation factor Xa (FXa). The presence of a haemostatic system in these snakes implies that they have two parallel prothrombin activating systems: one in the plasma, that participates in the life saving process of blood clotting and the other in their venom, where it acts as a toxin. Here, we report the complete cDNA sequence encoding the blood coagulation factor X (FX) from the liver of T. carinatus. Deduced T. carinatus FX sequence shows ~80% identity with trocarin D but ~50% identity with the mammalian FX. Our present study confirms the presence of two separate genes – one each for FX and trocarin D, that code for similar proteins in T. carinatus snake. These two genes have different expression sites and divergent uses suggesting that snake venom prothrombin activators have probably evolved by the duplication of the liver FX gene and subsequently marked for tissue-specific expression in the venom gland.

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