Inhibitors of Factor VIIa/Tissue Factor

Abstract

Abstract-The formation of the proteolytic complex composed of the serine protease Factor VIIa and the cell-associated glycoprotein tissue factor (FVIIa/TF) initiates a cascade of amplified zymogen activation reactions leading to thrombus formation. The critical role of the coagulation cascade in pathological thrombosis has been the basis for significant efforts to design selective inhibitors of the protease components as new anticoagulant alternatives for the treatment of thrombotic diseases. However, for the new generation of anticoagulant drugs in development that primarily target protease complexes distal from FVIIa/TF, the differential between efficacy and safety as defined by bleeding is unresolved. Targeting the FVIIa/TF complex has several theoretical advantages that exploit the amplified nature of the coagulation cascade. However, progress on the development of clinical-stage FVIIa/TF-based anticoagulants has not been as successful to date. This review summarizes recent efforts in the discovery of synthetic inhibitors of FVIIa/TF. Key Words: anticoagulants Ⅲ factor VIIa (FVIIa) Ⅲ tissue factor Ⅲ serine protease inhibitors Ⅲ coagulation H emostasis is achieved through a highly regulated and coordinated interplay of protein and cellular components designed to respond quickly to vascular insult. Critical in this rapid response is the initiation of blood coagulation by a proteolytic complex composed of the serine protease factor VIIa (FVIIa) and its cell-associated cofactor tissue factor (TF). Tissue factor is a transmembrane glycoprotein that is normally found in subendothelial structures throughout the vasculature. Exposure of TF to blood, through physical damage to the lining of the blood vessel or increased expression in endothelial and monocytic cells in response to certain inflammatory signals, permits an interaction with FVIIa, which is present at trace levels in the circulation. The formation of the FVIIa/TF complex is the critical step that initiates the sequentially amplified cascade of proteolytic activation steps that ultimately leads to the generation of the protease thrombin and thrombus formation. 1 The critical nature of the FVIIa/TF complex in the process of blood coagulation makes it an attractive candidate for the development of antithrombotic agents that can inhibit complex formation or catalytic activity. An antithrombotic agent based on the inhibition of FVIIa/TF may have theoretical advantages over the inhibition of downstream coagulation proteases such as factor Xa (FXa) or thrombin based on the several thousand-fold amplification that occurs after initiation by FVIIa/TF. The success of several small protein-and antibody-based inhibitors of the FVIIa/TF pathway in preclinical models and clinical trials 1,2 has led to substantial interest in the development of orally active small molecule inhibitors of the enzyme active site that could be used for the long-term prevention or treatment of thrombosis. Vitamin K antagonists such as warfarin, which have been used clinically for more than 5...

Exactin: A specific inhibitor of Factor X activation by extrinsic tenase complex from the venom of Hemachatus haemachatus

“…Among them, the ETC comprising of factor VIIa (FVIIa) and membrane-bound tissue factor (TF) play a crucial role in the clot initiation. The inhibition of this complex can control the thrombin burst and hence targeted for anticoagulant therapy13.…”

The Eph Tyrosine Kinase Receptors EphB2 and EphA2 Are Novel Proteolytic Substrates of Tissue Factor/Coagulation Factor VIIa

“…Based on the tryptic serine protease specificity of FVIIa with a requirement for an arginine residue at the P1 position (25) we concluded that cleavage by TF/FVIIa takes place at the Arg 155 -His 156 bond in EphA2. We performed sequence alignments of the cleavage area, which revealed that the key EphA2-Arg 159 residue was conserved in EphB2 but not in EphB3 or EphB4 (Fig.…”

“…Moreover, it is located in a part of the ligand-binding domain involved in high affinity interactions with ephrin ligands (33), further supporting that the cleavage site indeed is accessible for interactions with other proteins. Interestingly, the arginine residue at the cleavage site plays an important role in ephrin binding and forms a salt bridge with an aspartate residue in the ephrin ligand, similar to the FVIIa cleavage reaction where the acidic aspartate residue in the active site forms a salt bridge with the basic arginine residue in the scissile bond to be cleaved (25).…”

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