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The rapid global emergence of SARS-CoV-2 has been the cause of significant health concern, highlighting the immediate need for antivirals. Viral RNA-dependent RNA polymerases RdRp play essential roles in viral RNA synthesis, and thus remains the target of choice for the prophylactic or curative treatment of several viral diseases, due to high sequence and structural conservation. To date, the most promising broad-spectrum class of viral RdRp inhibitors are nucleoside analogues NAs , with over 25 approved for the treatment of several medically important viral diseases.

However, Coronaviruses stand out as a particularly challenging case for NA drug design due to the presence of an exonuclease ExoN domain capable of excising incorporated NAs and thus providing resistance to many of these available antivirals. We then map a promising NA candidate, GS the active metabolite of Remdesivir to the nucleoside active site of both proteins, identifying the residues important for nucleotide recognition, discrimination, and excision.

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