📄 Avoiding regions symptomatic of conformational and functional flexibility to identify antiviral targets in current and future coronaviruses

© The Author(s) 2016. Within the last 15 years, two related coronaviruses (Severe Acute Respiratory Syndrome [SARS]-CoV and Middle East Respiratory Syndrome [MERS]-CoV) expandedtheirhost range toincludehumans, with increased virulence intheirnewhost. Coronaviruseswere recently found to have little intrinsic disorder compared withmany other virus families. Because intrinsically disordered regions have been proposed to be important for rewiring interactionsbetweenvirus andhost,weinvestigatedthe conservationof intrinsic disorder and secondary structure in coronaviruses in an evolutionary context. We found that regions of intrinsic disorder are rarely conserved among different coronavirus protein families, with the primary exception of the nucleocapsid. Also, secondary structure predictions are only conserved across50-80%of sites for most protein families,with the implication that20-50%of sites do not have conserved secondary structure prediction. Furthermore, nonconserved structure sites are significantly less constrained in sequence divergence than either sites conserved in the secondary structure or sites conserved in loop. Avoiding regions symptomatic of conformational flexibility such as disordered sites and sites with nonconserved secondary structure to identify potential broad-specificity antiviral targets, onlyone sequencemotif (five residues or longer) remains from the >10,000 starting sites across all coronaviruses inthis study. Theidentifiedsequencemotif is foundwithin thenonstructuralprotein (NSP)12andconstitutesanantiviral targetpotentially effective against the presentdayand future coronaviruses. Onshorter evolutionary timescales, the SARSandMERSclades havemore sequence motifs fulfilling the criteria applied. Interestingly, many motifs map to NSP12 making this a prime target for coronavirus antivirals.

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