The use of anticoagulant drugs can cause acute complications, such as significant bleeding. So, despite limitations, such as a narrow therapeutic window, heparin is still a mainstay of current anticoagulant therapy because its actions can be reversed by using protamine, in contrast to other commonly used drugs, such as warfarin. Now, by selecting aptamers — single-stranded nucleic acids that can fold into intricate globular structures — for their ability to bind specifically to a procoagulant protein, Rusconi et al. have created an aptamer with anticoagulant effects that can be rapidly reversed using a rationally designed oligonucleotide 'antidote'.

The authors chose coagulation factor IXa (FIXa) as the target for aptamer generation, as animal studies had indicated that inhibitors of this protein might have a particularly favourable therapeutic window. Aptamers were created against FIXa using well-established techniques, and were assessed for their selectivity over several structurally similar proteins involved in the regulation of blood coagulation, including activated protein C, for which inhibition would promote blood coagulation. An aptamer with 5,000-fold selectivity for FIXa was identified, and in vitro plasma-clotting assays showed that it could inhibit FIXa activity in human plasma. Importantly for the potential clinical usefulness of such aptamers, attachment of a polyethylene-glycol chain to one end of the aptamer — a modification that considerably enhances its bioavailability — did not influence the anticoagulant activity of the aptamer significantly.

How could an antidote to this aptamer be produced? Aptamers fold into their globular structures through the formation of internal base pairs. So, the authors designed a series of oligonucleotides to compete for the crucial base pairs of the anticoagulant aptamer with the aim of disrupting its three-dimensional structure and thus its ability to bind to its target. Tests with human plasma showed that the oligonucleotides could rapidly reverse the effects of the anticoagulant aptamer, with their effectiveness being directly correlated with their ability to bind to the aptamer.

Translation of these promising in vitro results into in vivo animal models is eagerly awaited. And, in general, the development of aptamer–antidote pairs could prove particularly valuable for indications in which the acute side effects of treatment might lead to increased morbidity and mortality.