Modulation of the Coagulation Cascade Using Aptamers

Abstract

As a novel class of therapeutics, aptamers, or nucleic acid ligands, have garnered clinical interest due to the ease of isolating a highly specific aptamer against a wide range of targets, their chemical flexibility and synthesis, as well as their inherent ability to have their inhibitory ability 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.

The Intrinsic Pathway of Coagulation as a Target for Antithrombotic Therapy

“…75 They are selected for specific functional capabilities from pools of random RNA sequences. Aptamers can be regulated with a complementary oligonucleotide that neutralizes activity through Watson-Crick base pairing.…”

Evolution of Complex Target SELEX to Identify Aptamers against Mammalian Cell-Surface Antigens

“…For example, based on a study conducted by Watson et al, clearance of an aptamer against L-selectin could be modulated by simply modifying an aptamer with high-molecular-weight poly-(ethylene glycol) in vivo, utilizing animal models to reduce renal clearance and extend circulation time [ 14 ]. These properties are unique to aptamers, and they have been successfully utilized in designing new versatile molecules aimed at a multitude of applications [ 15 , 16 , 17 , 18 , 19 ]. Most importantly, recent advances in oligonucleotide-based therapeutics, such as antisense technology and microRNA therapeutics, have spurred a renewed demand for the development of novel aptamer-based targeting molecules [ 20 , 21 , 22 ].…”

Potential Inherent Stimulation of the Innate Immune System by Nucleic Acid Aptamers and Possible Corrective Approaches

“…Although some critics continue to question the future of aptamers, especially as pharmaceuticals, the future of aptamers still appears bright due to the advantages of aptamers over antibodies such as obviating host animals during development and production to reduce overall costs and greater batch to batch reproducibility and facile post-production modifications to “fine tune” performance [ 36 ]. There are so many promising applications for aptamers in the areas of enhanced drug delivery [ 37 ], therapy of antibiotic-resistant bacteria [ 38 , 39 , 40 ], deadly viruses [ 41 , 42 , 43 ], and cancers [ 44 , 45 ], inhibition of venoms [ 46 ] and biotoxins [ 47 ], regulation of blood clotting [ 48 ], drug transport across the blood-brain barrier [ 49 ], and stem cell differentiation or transdifferentiation induction [ 36 , 49 ], just to name a few potential uses. With so much promise in so many areas of critical medical need, the aptamer community cannot let CpG toxicity inhibit aptamer development progress.…”