Human coronaviruses (CoVs) – including the viruses associated with Severe Acute Respiratory Syndrome (SARS) and the recent Middle East Respiratory Syndrome (MERS) – can cause severe and lethal human disease, but no therapeutics or vaccines currently exist.

The CoV exoribonuclease (ExoN) protein, which is conserved across the CoV family, is required for high-fidelity replication of the viral RNA genome. In studies reported in PLOS Pathogens, Clint Smith, Ph.D., Mark Denison, M.D., and colleagues provide direct evidence that ExoN serves a “proofreading” (mistake correcting) function during replication. They showed that ExoN is responsible for CoV resistance to drugs that cause mutations. They found that CoVs lacking ExoN activity were up to 300-fold more sensitive to the RNA mutagen 5-fluorouracil – and had a16-fold increase in genomic mutations – compared to wild-type CoVs. CoVs without ExoN were also more sensitive to the anti-viral drug ribavirin.

The results suggest that small-molecule inhibitors of ExoN – especially in combination with RNA mutagens or ribavirin – could be potential therapeutics for treating CoV infections.

This research was supported by grants from the National Institutes of Health (AI057157, AI108197, AI095202) and from the European Union.