COVID-19 therapeutics and beyond: An HTS to identify inhibitors of SARS-CoV-2 nsp12 and starting points for other Coronavirus inhibitors

In the face of rapidly emerging viral pandemics, the normal commercial approach to antiviral translational research will not produce therapeutics in a timely manner. Consequently, there is an urgent need to prepare a strategic resource, openly available, to stimulate research into new antivirals for emerging viruses and, in an emergency situation, to provide compounds for expedited preclinical and human testing. Identification of collections of potent inhibitors of essential viral mechanisms within a virus family provides an excellent starting point for this accelerated transition to preclinical toxicity studies. Ultimately, we envisage libraries of 'poised' anti-coronavirus compounds would enable future responses to emerging pandemics as well as targeting SARS-CoV-2. We believe high throughput screening of a well-curated library enables this, with a focus on identification of robust chemical templates suitable for optimisation. We propose an HTS to identify non-nucleoside small molecules (mwt 200-450 Da) that inhibit the nsp12, the SARS-CoV-2 RdRp. Dependent upon the activity of our molecules, we will test our compounds against other coronavirus replicon systems or infectious virus. The coronavirus polymerase is a druggable antiviral target, conserved across the viral family. SARS-CoV RdRp and SARS-CoV-2 RdRp share a remarkable 96% identity. Morse et al (2020) comment that 'efforts towards drugging coronavirus in a RdRp manner should provide a basis not only to develop therapeutics for 2019-nCoV, but could provide broad-spectrum antivirals useful for future CoV outbreaks'. To that end we expect that classes of inhibitors identified by this proposal will have application across the coronavirus family.