Modulation of the Coagulation Cascade Using Aptamers

Abstract

As a novel class of therapeutics, aptamers, or nucleic acid ligands, have garnered clinical interest because of the ease of isolating a highly specific aptamer against a wide range of targets, their chemical flexibility and synthesis, and their inherent ability to have their function reversed. The following review details the development and molecular mechanisms of aptamers targeting specific proteases in the coagulation cascade. The ability of these anticoagulant aptamers to bind to and inhibit exosite function rather than binding within the active site highlights the importance of exosites in blocking protein function. As both exosite inhibitors and reversible agents, the use of aptamers is a promising strategy for future therapeutics.

Keywords: anticoagulation; aptamer; coagulation cascade; nucleic acids; serine endopeptidases.

Figure 1. Mechanisms of aptamer inhibition of the coagulation cascade

A. Aptamers inhibit the serine proteases of the coagulation cascade by binding to exosites and either disrupting cofactor binding (long dashed line), downstream zymogen binding (solid line), or activation of itself (short dashed line) leading to inhibited or reduced activation of the downstream zymogen, and thus reducing fibrin formation. B. An example of an aptamer (11F7t) disrupting cofactor binding by inhibiting FVa to bind to FXa, leading to a reduction in the amount of thrombin formed. C. An example of an aptamer (9.3t) disrupting zymogen binding by inhibiting FX binding to FIXa, leading to an inhibition of FX activation. FIXa binding to its cofactor FVIIIa is still intact.