Generation of an anticoagulant aptamer that targets factor V/Va and disrupts the FVa-membrane interaction in normal and COVID-19 patient samples.

Journal Article (Journal Article)

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 (FV) and 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 patients with coronavirus disease 2019 (COVID-19). 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 interactions 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 an unconventional working mechanism of an aptamer by interrupting protein-membrane interactions.

Full Text

Duke Authors

Cited Authors

  • Soule, EE; Yu, H; Olson, L; Naqvi, I; Kumar, S; Krishnaswamy, S; Sullenger, BA

Published Date

  • February 17, 2022

Published In

Volume / Issue

  • 29 / 2

Start / End Page

  • 215 - 225.e5

PubMed ID

  • 35114109

Pubmed Central ID

  • PMC8808741

Electronic International Standard Serial Number (EISSN)

  • 2451-9448

Digital Object Identifier (DOI)

  • 10.1016/j.chembiol.2022.01.009

Language

  • eng

Conference Location

  • United States