Therapeutic Aptamers and Antidotes: A Novel Approach to Safer Drug Design

Abstract

Certain RNA molecules can adopt highly ordered three-dimensional structures that allow them to bind to target proteins with high affinity and specificity. This facet of RNA biochemistry is now being utilized to develop a novel class of therapeutic agents based upon RNA ligands. We and others originally demonstrated that small RNA ligands, originally termed decoys, could inhibit the activity of essential HIV RNA-binding proteins and impede viral replication. Subsequent work demonstrated that this concept of using RNA ligands as inhibitors could be greatly extended because such RNA ligands, renamed aptamers, could be generated to inhibit the activity of virtually any protein by using in vitro selection and combinatorial chemistry methods. We recently demonstrated that antidotes can be rationally designed to reverse the activity of aptamers, raising the possibility that aptamers may represent a unique class of therapeutic agents that have an important safety advantage over other therapeutic classes of molecules. Toward this end, we have demonstrated that the anticoagulant activity of an aptamer targeting coagulation factor IXa can be quickly and efficiently reversed by complementary oligonucleotides that can act as antidotes to the aptamer.