Target-directed dynamic combinatorial chemistry affords inhibitors of Nsp10 as potential antivirals against SARS-CoV-2

The development of antiviral drugs against the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) responsible for the recent worldwide Covid-19 pandemic is important, as treatment options are still very limited and vaccination largely does not prevent infection. Two underexplored potential targets of this virus are the 3to5 exoribonuclease (ExoN) and the 2-O-methyltransferase (2-O-Mtase), which are essential for the viability of the virus. The non-structural protein Nsp14 displays the first enzymatic activity, and Nsp16 the latter, especially while in complex with their co-factor protein Nsp10. Herein, we report the use of target-directed dynamic combinatorial chemistry to find binders of Nsp10, in the aim of preventing the formation of the Nsp10-Nsp14 and Nsp10-Nsp16 protein-protein interaction (PPI). We synthesised the hits, and tested them for their affinity Nsp10 affinity, their inhibition of ExoN and 2-O-methyltransferase activities, as well as their anti-viral potential in a hCoV-229E and SARS-CoV-2 whole-cell setting. We report a novel class of inhibitors of ExoN and/or 2-O-methyltransferase activities that present an anti-viral activity against coronaviruses.