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by Leigh MacMillan | Thursday, Sep. 12, 2013, 8:00 AM
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.
Leigh MacMillan, (615) 322-4747
Health and Medicine, Reporter, Research Aliquots, coronavirus, Elizabeth B. Lamb Center for Pediatric Research, Mark Denison, NIAID, NIH, pathology microbiology and immunology, pediatrics, PLoS Pathogens, Reporter Sept 13 2013, SARS
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