RNA aptamers as reversible antagonists of coagulation factor IXa
RNA aptamers as reversible antagonists of coagulation factor IXa
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DOI：
10.1038/nature00963
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发表时间：
2002-09-05
期刊：
影响因子：
64.8
通讯作者：
Sullenger, BA
中科院分区：
文献类型：
--
作者：
Rusconi, CP;Scardino, E;Sullenger, BA
许多治疗药物与患者的不良反应有关。抗凝剂可引起急性并发症，如大出血，增加患者的发病率和死亡率(1)。解毒剂控制是调节药物作用的最安全手段。因此，尽管肝素有其已知的局限性和毒性，但它的使用率仍然很高，因为它是唯一一种可以通过解毒剂多肽鱼精蛋白来控制的抗凝血剂（2-4）。迄今为止，尚未描述开发药物解毒剂对的通用策略。我们研究了能否利用核酸固有的特性合理设计药物-解毒剂对来制作解毒剂控制的抗凝剂。在这里，我们证明了抗凝血因子IXa的蛋白结合寡核苷酸（适体）是有效的抗凝血剂。我们还发现，与这些适体互补的寡核苷酸可以作为解毒剂，有效地逆转健康志愿者和不能耐受肝素的患者血浆中这些新型抗凝血剂的活性(5)。因此，这种合理设计药物解毒剂对的可推广策略为开发更安全的可调节疗法开辟了道路。
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(1). 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(2-4). 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(5). This generalizable strategy for rationally designing a drug-antidote pair thus opens up the way for developing safer regulatable therapeutics.