Glutamate ion channels have three subtypes, that is, α-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA), kainate, and N-methyl-d-aspartate (NMDA) receptors. Excessive activity of these receptor subtypes either individually or collectively is involved in various neurological disorders. RNA aptamers as antagonists of these receptors are potential therapeutics. For developing aptamer therapeutics, the RNA aptamers must be chemically modified to become ribonuclease-resistant or stable in biological fluids. Using systematic evolution of ligands by exponential enrichment (SELEX) and a chemically modified library, prepared enzymatically (i.e., the library contains RNAs with 2′-fluoro modified nucleoside triphosphates or ATPs, CTPs and UTPs, but regular GTPs), we have isolated an aptamer. The short aptamer (69 nucleotides) FN1040s selectively inhibits the GluA1 and GluA2Q_flip AMPA receptor subunits, whereas the full-length aptamer (101 nucleotides) FN1040 additionally inhibits GluK1, but not GluK2, kainate receptor, and GluN1a/2A and GluN1a/2B, the two major native NMDA receptors. The two aptamers show similar potency (2–4 μM) and are stable with a half-life of at least 2 days in serum-containing medium or cerebrospinal fluid. Therefore, these two aptamers are amenable for in vivo use.

中文翻译：

---

化学修饰，α氨基-3-羟基-5-甲基-4-异恶唑（AMPA）受体RNA适体设计用于在体内使用

谷氨酸离子通道具有三种亚型，即α-氨基-3-羟基-5-甲基-4-异恶唑（AMPA），海藻酸盐和N-甲基-d-天冬氨酸（NMDA）受体。这些受体亚型的单独或共同的过度活性与多种神经系统疾病有关。RNA适体作为这些受体的拮抗剂是潜在的治疗方法。为了开发适体疗法，必须对RNA适体进行化学修饰以使其对核糖核酸酶具有抵抗力或在生物体液中稳定。使用通过指数富集（SELEX）进行的配体的系统进化和以酶法制备的化学修饰的文库（即，该文库包含具有2'-氟修饰的三磷酸核苷或ATP的RNA，CTP和UTP，但有常规GTP），适体。短适体（69个核苷酸）FN1040s选择性抑制GluA1和GluA2Q_翻转AMPA受体亚基，而全长适体（101个核苷酸）FN1040另外抑制GluK1，但不抑制海藻酸酯受体GluK2，以及两种主要的天然NMDA受体GluN1a / 2A和GluN1a / 2B。两种适体显示出相似的效价（2-4μM），并且在含血清的培养基或脑脊髓液中具有至少2天的半衰期稳定。因此，这两种适体适合于体内使用。