Discovery of Photoexcited 2‐Chloro‐3,5‐Dinitrobenzoic Acid as a Chemical Deprenylase of i6A RNA

Abstract

AbstractRNA modifications play crucial roles in regulating gene expression and cellular homeostasis. Modulating RNA modifications, particularly by targeting the enzymes responsible for their catalysis, has emerged as a promising therapeutic strategy. However, limitations, such as the lack of identified modifying enzymes and compensatory mechanisms, hinder targeted interventions. Chemical approaches independent of enzymatic activity offer an alternative strategy for RNA modification modulation. Here, we present the identification of 2‐chloro‐3,5‐dinitrobenzoic acid as a highly effective photochemical deprenylase of i6A RNA. This method demonstrates exceptional selectivity towards i6A, converting its substituent into a “N‐doped” ozonide, which upon hydrolysis releases natural adenine. We believe that this chemical approach will pave the way for a better understanding of RNA modification biology and the development of novel therapeutic modalities.