Structure-based design of TAV2b-derived RNA modulators

Abstract Ribonucleic acids (RNAs) are increasingly being recognized as an attractive therapeutic target. However, their intrinsic structural flexibility and lack of well-defined binding pockets cause significant challenges for the design of high-affinity modulators. In nature, RNA–protein interactions play key roles in important cellular functions, rendering RNA-binding proteins ideal templates for developing RNA-targeting peptides. Herein, we review structure-based design strategies inspired by the Tomato Aspermy Virus protein 2b (TAV2b), highlighting key design strategies to enhance affinity and selectivity as well as bioactivity. These approaches demonstrate how structure-guided design and chemical assembly strategies can address the challenges associated with the development of bioactive RNA binders. Expanding these strategies will accelerate the exploitation of RNA as a target in drug discovery and diagnostics.