Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA.
Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA; Chimerna Therapeutics, New York, NY 10032, USA.
Cell Chem Biol. 2024 Oct 17;31(10):1827-1838.e7. doi: 10.1016/j.chembiol.2024.07.017. Epub 2024 Aug 26.
Small molecule-regulated RNA devices have the potential to modulate diverse aspects of cellular function, but the small molecules used to date have potential toxicities limiting their use in cells. Here we describe a method for creating drug-regulated RNA nanodevices (RNs) using acyclovir, a biologically compatible small molecule with minimal toxicity. Our modular approach involves a scaffold comprising a central F30 three-way junction, an integrated acyclovir aptamer on the input arm, and a variable effector-binding aptamer on the output arm. This design allows for the rapid engineering of acyclovir-regulated RNs, facilitating temporal, tunable, and reversible control of intracellular aptamers. We demonstrate the control of the Broccoli aptamer and the iron-responsive element (IRE) by acyclovir. Regulating the IRE with acyclovir enables precise control over iron-regulatory protein (IRP) sequestration, consequently promoting the inhibition of ferroptosis. Overall, the method described here provides a platform for transforming aptamers into acyclovir-controllable antagonists against physiologic target proteins.
小分子调控的 RNA 器件具有调节细胞功能多样化的潜力，但迄今为止使用的小分子具有潜在的毒性，限制了它们在细胞中的应用。在这里，我们描述了一种使用阿昔洛韦（一种具有最小毒性的生物相容小分子）创建药物调控 RNA 纳米器件（RN）的方法。我们的模块化方法涉及一个支架，该支架由中央 F30 三向连接组成，输入臂上集成了阿昔洛韦适体，输出臂上则是可变的效应物结合适体。这种设计允许快速工程化阿昔洛韦调控的 RN，实现对细胞内适体的时间、可调谐和可逆控制。我们展示了阿昔洛韦对西兰花适体和铁反应元件（IRE）的控制。通过阿昔洛韦调节 IRE，可以精确控制铁调节蛋白（IRP）的隔离，从而促进铁死亡的抑制。总的来说，这里描述的方法为将适体转化为针对生理靶蛋白的阿昔洛韦可控拮抗剂提供了一个平台。
