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bioRxiv · 10.1101/2021.04.07.438808

Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp13 Helicase

Beale, R.·Bertolin, A. P.·Borg, A.·Canal, B.·Diffley, J. F.·Drury, L. S.·Harvey, R.·Howell, M.·Hussain, S.·Kjaer, S.·McCauley, J.·McCoy, L.·Milligan, J.·Posse, V.·Roustan, C.·Ulferts, R.·Weissmann, F.·Wu, M.·Zeng, J.
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Abstract

The coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global public health challenge. While the efficacy of vaccines against emerging and future virus variants remains unclear, there is a need for therapeutics. Repurposing existing drugs represents a promising and potentially rapid opportunity to find novel antivirals against SARS-CoV-2. The virus encodes at least nine enzymatic activities that are potential drug targets. Here we have expressed, purified and developed enzymatic assays for SARS-CoV-2 nsp13 helicase, a viral replication protein that is essential for the coronavirus life cycle. We screened a custom chemical library of over 5000 previously characterised pharmaceuticals for nsp13 inhibitors using a FRET-based high-throughput screening (HTS) approach. From this, we have identified FPA-124 and several suramin-related compounds as novel inhibitors of nsp13 helicase activity in vitro. We describe the efficacy of these drugs using assays we developed to monitor SARS-CoV-2 growth in Vero E6 cells.

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Beale, R., Bertolin, A. P., Borg, A., Canal, B., Diffley, J. F., Drury, L. S., Harvey, R., Howell, M., Hussain, S., Kjaer, S., McCauley, J., McCoy, L., Milligan, J., Posse, V., Roustan, C., Ulferts, R., Weissmann, F., Wu, M., Zeng, J.. 2021-04-08. Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp13 Helicase. https://doi.org/10.1101/2021.04.07.438808

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