Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp14/nsp10 exoribonuclease.
journal contributionposted on 09.07.2021, 08:47 by Berta Canal, Allison W McClure, Joseph F Curran, Mary Wu, Rachel Ulferts, Florian Weissmann, Jingkun Zeng, Agustina P Bertolin, Jennifer C Milligan, Souradeep Basu, Lucy S Drury, Tom D Deegan, Ryo Fujisawa, Emma L Roberts, Clovis Basier, Karim Labib, Rupert Beale, Michael Howell, John FX Diffley
SARS-CoV-2 is a coronavirus that emerged in 2019 and rapidly spread across the world causing a deadly pandemic with tremendous social and economic costs. Healthcare systems worldwide are under great pressure, and there is an urgent need for effective antiviral treatments. The only currently approved antiviral treatment for COVID-19 is remdesivir, an inhibitor of viral genome replication. SARS-CoV-2 proliferation relies on the enzymatic activities of the non-structural proteins (nsp), which makes them interesting targets for the development of new antiviral treatments. With the aim to identify novel SARS-CoV-2 antivirals, we have purified the exoribonuclease/methyltransferase (nsp14) and its cofactor (nsp10) and developed biochemical assays compatible with high-throughput approaches to screen for exoribonuclease inhibitors. We have screened a library of over 5000 commercial compounds and identified patulin and aurintricarboxylic acid (ATA) as inhibitors of nsp14 exoribonuclease in vitro. We found that patulin and ATA inhibit replication of SARS-CoV-2 in a VERO E6 cell-culture model. These two new antiviral compounds will be valuable tools for further coronavirus research as well as potentially contributing to new therapeutic opportunities for COVID-19.
Crick (Grant ID: 10827, Grant title: Beale FC001827) Crick (Grant ID: 10066, Grant title: Diffley FC001066) Crick (Grant ID: 10008, Grant title: STP High Throughput Screening) Wellcome Trust (Grant ID: 106252/Z/14/Z, Grant title: WT 106252/Z/14/Z) European Commission (Grant ID: 844211 - HUMAN REPL MECH, Grant title: EC 844211 - HUMAN REPL MECH) Crick (Grant ID: 10121, Grant title: Nurse FC001121)
AnimalsAntiviral AgentsAurintricarboxylic AcidChlorocebus aethiopsDrug Evaluation, PreclinicalEnzyme AssaysExoribonucleasesFluorescenceHigh-Throughput Screening AssaysPatulinReproducibility of ResultsSARS-CoV-2Small Molecule LibrariesVero CellsViral Nonstructural ProteinsViral Regulatory and Accessory ProteinsDiffley FC001066Beale FC001827Nurse FC001121HTSFERM-ack03 Chemical Sciences06 Biological Sciences11 Medical and Health SciencesBiochemistry & Molecular Biology