3'-to-5' exoribonuclease (ExoN)

3'-to-5' exoribonucleases (ExoNs) are a diverse family of enzymes that catalyze the processive hydrolysis of RNA from the 3' terminus, playing essential roles in RNA maturation, surveillance, and degradation. In human cells, the most prominent members include the catalytic subunits of the exosome complex, such as DIS3 and EXOSC10, which regulate the turnover of mRNA, rRNA, and various non-coding RNAs to maintain cellular homeostasis (Source [7, 14]). In virology, coronaviruses like SARS-CoV-2 encode a highly conserved 3'-5' exoribonuclease within Non-structural protein 14 (nsp14) that performs a critical proofreading function during genome replication (Source [3, 11]). This activity is vital for maintaining the integrity of large viral genomes by excising misincorporated nucleotides and several chain-terminating nucleoside analogs, such as remdesivir, which would otherwise halt replication (Source [1, 22]). Therapeutically, 3'-5' exoribonucleases are high-value targets for both antiviral and oncology applications. Inhibitors of the viral nsp14-ExoN, including repurposed drugs like pibrentasvir and ombitasvir, are being investigated for their ability to sensitize the virus to nucleoside analogs and mutagenic agents (Source [12, 22]). In oncology, mutations in the human exoribonuclease DIS3 are observed in roughly 10-11% of multiple myeloma cases, where they impact the transcriptional landscape and serve as potential biomarkers for disease progression and therapeutic vulnerability (Source [11, 13]). A significant therapeutic challenge lies in the high structural conservation of the DEDDh/DEEDh catalytic motifs across the ExoN family, which requires drug candidates to achieve high selectivity for viral or tumor-specific enzymes to avoid toxic off-target disruption of essential human RNA metabolism (Source [5, 9]).

Other names

3'-5' ExoribonucleaseExoNExoribonucleaseProofreading exonucleaseRNase II-like ribonuclease

Direct inhibition of 3'-to-5' exoribonuclease catalytic activity or disruption of the stoichiometric complex between the exoribonuclease and its essential accessory/activation proteins (e.g., nsp14-nsp10 or the exosome core).