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RNA aptamers as reversible antagonists of coagulation factor IXa.
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- Author(s): Rusconi CP;Rusconi CP; Scardino E; Layzer J; Pitoc GA; Ortel TL; Monroe D; Sullenger BA
- Source:
Nature [Nature] 2002 Sep 05; Vol. 419 (6902), pp. 90-4.- Publication Type:
Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.- Language:
English - Source:
- Additional Information
- Source: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print Cited Medium: Print ISSN: 0028-0836 (Print) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE
- Publication Information: Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd. - Subject Terms: Drug Design*; Anticoagulants/*antagonists & inhibitors ; Anticoagulants/*pharmacology ; Antidotes/*pharmacology ; Factor IXa/*antagonists & inhibitors ; Oligoribonucleotides/*pharmacology ; RNA/*pharmacology; Anticoagulants/chemistry ; Anticoagulants/metabolism ; Antidotes/chemistry ; Antidotes/metabolism ; Base Sequence ; Binding, Competitive/drug effects ; Contraindications ; Factor IXa/metabolism ; Factor VIIIa/metabolism ; Factor X/metabolism ; Heparin/pharmacology ; Humans ; Molecular Sequence Data ; Nucleic Acid Conformation ; Oligoribonucleotides/antagonists & inhibitors ; Oligoribonucleotides/genetics ; Oligoribonucleotides/metabolism ; Partial Thromboplastin Time ; Prothrombin Time ; RNA/antagonists & inhibitors ; RNA/genetics ; RNA/metabolism ; Thrombocytopenia/chemically induced
- Abstract: Many therapeutic agents are associated with adverse effects in patients. Anticoagulants can engender acute complications such as significant bleeding that increases patient morbidity and mortality. Antidote control provides the safest means to regulate drug action. For this reason, despite its known limitations and toxicities, heparin use remains high because it is the only anticoagulant that can be controlled by an antidote, the polypeptide protamine. To date, no generalizable strategy for developing drug-antidote pairs has been described. We investigated whether drug-antidote pairs could be rationally designed by taking advantage of properties inherent to nucleic acids to make antidote-controlled anticoagulant agents. Here we show that protein-binding oligonucleotides (aptamers) against coagulation factor IXa are potent anticoagulants. We also show that oligonucleotides complementary to these aptamers can act as antidotes capable of efficiently reversing the activity of these new anticoagulants in plasma from healthy volunteers and from patients who cannot tolerate heparin. This generalizable strategy for rationally designing a drug-antidote pair thus opens up the way for developing safer regulatable therapeutics.
- Comments: Comment in: Nature. 2002 Sep 5;419(6902):23-4. (PMID: 12214216)
- Accession Number: 0 (Anticoagulants)
0 (Antidotes)
0 (Oligoribonucleotides)
63231-63-0 (RNA)
72175-66-7 (Factor VIIIa)
9001-29-0 (Factor X)
9005-49-6 (Heparin)
EC 3.4.21.22 (Factor IXa) - Publication Date: Date Created: 20020906 Date Completed: 20021004 Latest Revision: 20220705
- Publication Date: 20221213
- Accession Number: 10.1038/nature00963
- Accession Number: 12214238
- Source:
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