XNAzymes targeting the SARS-CoV-2 genome inhibit viral infection

The unprecedented emergence and spread of SARS-CoV-2 underscores the need for diagnostic and therapeutic technologies that can be rapidly tailored to novel threats. Here, we show that site-specific RNA endonuclease XNAzymes—artificial catalysts composed of single-stranded synthetic xeno-nucleic acid oligonucleotides (2′-deoxy-2′-fluoro-β-D-arabino nucleic acid, FANA)—can be designed, synthesized, and screened within days to target multiple regions of the SARS-CoV-2 genome (ORF1ab, ORF7b, spike, and nucleocapsid). Three XNAzymes were further engineered to self-assemble into a catalytic nanostructure with enhanced biosafety and biostability. These XNAzymes cleave genomic SARS-CoV-2 RNA under physiological conditions and inhibit infection with authentic SARS-CoV-2 in cells via RNA knockdown. The results demonstrate the potential of XNAzymes as a platform for rapid generation of antiviral reagents.