Non-structural protein 14 (nsp14) exoribonuclease (ExoN) catalytic site (nsp14 ExoN)

SARS-CoV-2 non-structural protein 14 (nsp14) is a bifunctional enzyme essential for viral replication and fitness (UniProt P0DTD1). It contains an N-terminal 3'-to-5' exoribonuclease (ExoN) domain and a C-terminal N7-methyltransferase (N7-MTase) domain (Robson et al., 2020). The ExoN catalytic site is responsible for the high-fidelity replication of the large coronavirus genome by performing a proofreading function, where it removes mismatched nucleotides incorporated by the RNA-dependent RNA polymerase, nsp12 (Ferron et al., 2018). This activity makes the virus inherently resistant to many nucleoside analog antivirals, such as Ribavirin, as the ExoN can excise these drugs from the nascent RNA strand (Smith et al., 2013). Targeting the ExoN catalytic site is a promising therapeutic strategy to enhance the efficacy of existing antivirals like Remdesivir or to induce 'lethal mutagenesis' in the virus by increasing its mutation frequency beyond a sustainable threshold (Moeller et al., 2022).

Other names

nsp14ExoN3'-to-5' exoribonucleaseSARS-CoV-2 nsp14Proofreading exonucleaseGuanine-N7-methyltransferase/3'-5' exoribonuclease

Inhibition of the 3'-to-5' exoribonuclease activity to prevent the removal of mismatched or therapeutic nucleoside analogs from the viral RNA, thereby increasing the mutation rate or allowing chain termination to proceed effectively.