北京大学张力勤团队报道了核内阻断RNA-蛋白相互作用的功能适体体外演变。相关研究成果于2024年8月21日发表在《美国化学会杂志》。

在过去的30年里，旨在利用适配体作为药物分子尽管进行了大量的研究和努力，但开发基于适配体的药物的进展一直低于预期。研究发现，基于亲和力的大分子疗法通常需要亲和分子获取和功能筛选的连续步骤，这可能很耗时，并且在候选药物选择方面存在限制。此外，适配体通常需要繁琐的选后修饰来克服药代动力学限制，这通常会阻碍结合亲和力。

该文中，研究人呢呀提出了一种新的体外筛选平台，称为功能性适配体体外演变（FAIVE），该平台将亲和分子获取与功能筛选相结合，并在过程中引入了化学多样性。该平台旨在快速生成能够结合靶蛋白并调节其功能的功能性适配体。

通过靶向涉及HIV-1 Tat蛋白和TAR RNA的核内RNA-蛋白相互作用，FAIVE展示了一系列具有显著细胞内阻断作用的功能性适配体。该研究还探索了脂质纳米粒子递送系统，以提高细胞内递送效率，将适配体靶向潜力扩展到更广泛的细胞内和核内结构域。

该研究强调了FAIVE在加快基于适配体的药物开发，和促进创建更通用和有效的治疗方法方面的潜力。

附：英文原文

Title: Functional Aptamers In Vitro Evolution for Intranuclear Blockage of RNA-Protein Interaction

Author: Jun Li, Panzhu Yao, Ke Tang, Xuyang Zhao, Xiyang Liu, Qinguo Liu, Tongxuan Wei, Hong Xuan, Siqi Bian, Ying Guo, Zhenjun Yang, Zhi-Qi Zhang, Liqin Zhang

Issue&Volume: August 21, 2024

Abstract: Over the last 30 years, despite considerable research and endeavors aimed at harnessing aptamers as pharmaceutical molecules, the progress in developing aptamer-based drugs has been falling short of expectations. Sequential steps of affinity molecule acquisition and functional screening are typically required for discovering affinity-based macromolecule therapeutics, which can be time-consuming and limiting in candidate selection. Additionally, aptamers often necessitate tedious postselection modifications to overcome pharmacokinetic limitations, which usually impede the binding affinity. Herein, we propose a novel in vitro screening platform termed Functional Aptamers in vitro Evolution (FAIVE), which integrates affinity molecule acquisition with functional screening and introduces chemical diversity during the process. This platform aims to rapidly generate functional aptamers capable of binding to target proteins and regulating their functions. Illustrated by targeting intranuclear RNA-protein interactions involving HIV-1 Tat protein and TAR RNA, FAIVE demonstrates a selection of functional aptamers with significant intracellular blocking effects. The study also explores lipid nanoparticle delivery systems to enhance intracellular delivery efficiency, expanding aptamer targeting potential to broader intracellular and intranuclear domains. This study emphasizes the potential of FAIVE to expedite the development of aptamer-based drugs and facilitate the creation of more versatile and effective therapeutics.

DOI: 10.1021/jacs.4c08824

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.4c08824