Targeted Degradation of Structured RNAs via Ribonuclease-Targeting Chimeras (RiboTacs)

RNA structural motifs can serve as recognition sites for proteins or regulatory elements. Notably, these specific RNA shapes are directly related to many diseases. Targeting specific RNA motifs using small molecules is an emerging domain of study within the area of drug discovery. Targeted degradation strategies are a relatively modern technology in drug discovery, offering important clinical and therapeutic outcomes. These approaches involve using small molecules to selectively degrade specific biomacromolecules associated with a disease. "Ribonuclease-Targeting Chimeras" (RiboTaCs) represent a promising type of targeted degradation strategy due to their ability to selectively degrade structured RNA targets.In this review, the authors present the evolution of RiboTaCs, their underlying mechanism, and their in-vitro validation. The authors summarize several disease-associated RNAs that have been previously targeted for degradation using the RiboTaC strategy and discuss how their degradation led to alleviating disease-associated phenotypes in-vitro and in-vivo.There are several future challenges that still need to be adressed for RiboTaC technology to fully realize its potential. Despite these challenges, the authors are optimistic about its prospects, which have the potential to fundamentally transform the treatment of a wide range of diseases.