Generation of an Anticoagulant Aptamer that Targets Factor V/Va and Disrupts the FVa-Membrane Interaction in Normal and COVID-19 Patient Samples. Soule et al
Description
Coagulation cofactors profoundly regulate hemostasis and are appealing targets for anticoagulants. However, targeting such proteins has been challenging because they lack an active site. To address this, we isolate an RNA aptamer termed T18.3 that binds to both Factor V and Va (FV/FVa) with nanomolar affinity and demonstrates clinically relevant anticoagulant activity in both plasma and whole blood. The aptamer also shows synergy with low molecular weight heparin, and delivers potent anticoagulation in plasma collected from COVID-19 patients. Moreover, the aptamer's anticoagulant activity can be rapidly and efficiently reversed using protamine sulfate, which potentially allows fine-tuning of aptamer’s activity post-administration. We further show that the aptamer achieves its anticoagulant activity by abrogating FV/FVa interaction with phospholipid membranes. Our success in generating an anticoagulant aptamer targeting FV/Va demonstrates the feasibility of using cofactor-binding aptamers as therapeutic protein-inhibitors and reveals a unconventional working mechanism of aptamer by interrupting protein-membrane interactions.