Bioorthogonal RNase L Recruitment Enables Targeted Inducible Degradation of SARS‐CoV‐2 RNA

Abstract RIBOTAC (Ribonuclease Targeting Chimera) is a strategy that employs small molecules to selectively bind disease‐associated RNA and recruit endogenous RNase L for targeted RNA degradation. This study advances the concept of bioorthogonal cleavage reactions to develop a novel “bioorthogonal RIBOTAC” (boRIBOTAC). Focusing on SARS‐CoV‐2 viral RNA, we engineered a cleavable “cage” protective group into a critical site within the RIBOTAC molecule, rendering it inactive as ProRIBOTAC in its untriggered state. When therapeutic intervention becomes necessary or disease progression demands it, a bioorthogonal cleavage reaction selectively removes the protective group, activating the RIBOTAC and thus facilitating inducible degradation of SARS‐CoV‐2 RNA. This research not only validates the feasibility of this boRIBOTAC and the inducible SARS‐CoV‐2 RNA degradation strategy but also demonstrates that the boRIBOTAC approach is poised to construct a controllable and effective RNA degradation platform. This platform is anticipated to provide significant technical reserves and practical prospects for addressing potential viral pandemics, chronic infections, and complex disease progressions, while also offering critical insights for future RNA‐targeted drug design.