Fig. 6. Small-molecule RNA degraders and their mechanisms of action.

a | Degraders can elicit biological functions even if bound to non-functional sites within the RNA target as they cleave the transcript. Simply binding to non-functional sites is in principle biologically silent. Notably, degraders cleave RNA targets sub-stoichiometrically, as the same degrader molecule can cleave more than one RNA transcript by substrate turnover and can be optimized to improve target selectivity, including linker length, substrate preference and cellular localization of the target. b | Mechanisms of small-molecule-facilitated degradation. From left to right: small molecules can bind to intronic RNA repeat expansions that are harboured as retained introns. This causes excision of the intron, which is decayed by the RNA exosome²⁸⁰; RNA-binding compounds can be appended to natural products such as bleomycin that can cause oxidative cleavage of RNA targets selectively; ribonuclease-targeting chimeras induce the proximity of ribonucleases to unnaturally target an RNA for destruction by native quality control pathways; and small molecules can affect pre-mRNA splicing to create a mature mRNA with included exons that contain premature termination codons that trigger decay via nonsense-mediated decay. RNase, ribonuclease.