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DOI: 10.1160/TH06-01-0047
A potent anti-coagulant RNA aptamer inhibits blood coagulation by specifically blocking the extrinsic clotting pathway
Financial support: This work was supported by funds from the National Institute of Industrial Science and Technology (AIST) to PKRK and from the New Energy and Industrial Technology Development Organization (NEDO) to HM. SCBG is supported by the Japan Society for the Promotion of Science (JSPS).
Publikationsverlauf
Received
24. Januar 2006
Accepted after revision
17. März 2006
Publikationsdatum:
02. Dezember 2017 (online)
Summary
A potent antidote-controlled aptamer, as an anticoagulant, has reportedly overcome the complications of acute bleeding by the administration of available anticoagulants. In the present study, we provide evidence that the aptamer binds specifically to factors IX and IXa and inhibits their functions. Furthermore, we demonstrated that the aptamer inhibits blood coagulation by interfering with the extrinsic pathway, blocking the complex of factor VIIa and tissue factor interactions with factor IX. The results from the previous and present studies suggest that the aptamer probably binds in the vicinity of the EGF1 and EGF2 domains of factor IX.
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References
- 1 Shikamoto Y, Morita T, Fujimoto Z. et al. Crystal structure of Mg2+ and Ca2+ -bound Gla domain of factor IX complexed with binding protein. J Biol Chem 2003; 278: 24090-4.
- 2 Weitz JI, Crowther MA. New anticoagulants: current status and future potential. Am J Cardiovasc Drugs 2003; 03: 201-9.
- 3 Becker RC, Rusconi C, Sullenger BA. Nucleic acid aptamers in therapeutic anticoagulation: technology, development and clinical application. Thromb Haemost 2005; 93: 1014-20.
- 4 Hirsch J, Anand SS, Halperin JL, Fuster V. Guide to anticoagulant therapy: Heparin:A statement for healthcare professionals from the American Heart Association. Circulation 2001; 103: 2994-3018.
- 5 Rusconi CP, Scardino E, Layzer J. et al. RNA aptamers as reversible antagonists of coagulation factor IXa. Nature 2002; 419: 90-4.
- 6 Rusconi CP, Roberts JD, Pitoc GA. et al. Antidotemediated control of an anticoagulant aptamer in vivo . Nature Biotech 2004; 22: 1423-8.
- 7 Nimjee SM, Rusconi CR, Sullenger BA. Aptamers: an emerging class of therapeutics. Ann Rev Med 2005; 56: 555-83.
- 8 Nimjee SM, Rusconi CP, Harrington RA. et al. The potential of aptamers as anticoagulants. Trends Card Med 2005; 15: 41-5.
- 9 Seiwert SD, Nahreini TS, Aigner S. et al. RNA aptamers as pathway-specific MAP kinase inhibitors. Chem Biol 2000; 07: 833-43.
- 10 Komiyama Y, Pedersen AH, Kisiel W. Proteolytic activation of human factors IX and X by recombinant human factor VIIa: effects of calcium, phospholipids, and tissue factor. Biochemistry 1990; 29: 9418-25.
- 11 Chen SW, Pellequer JL, Schved JF. et al. Model of a ternary complex between activated factor VII, tissue factor and factor IX. Thromb Haemost 2000; 88: 74-82.
- 12 Schmidt AE, Bajaj SP. Structure-function relationships in factor IX and factor IXa. Trends Card Med 2003; 13: 39-45.