The functional importance of M pro in the viral life cycle, combined with the absence of closely related homologues in humans, identify M pro as an attractive target for the design of antiviral drugs 9. M pro digests the polyprotein at at least 11 conserved sites, starting with the autolytic cleavage of this enzyme itself from pp1a and pp1ab 8. The functional polypeptides are released from the polyproteins by extensive proteolytic processing, predominantly by the 33.8-kDa M pro (also known as 3C-like protease). The SARS-CoV-2 genome comprises about 30,000 nucleotides: the replicase gene of SARS-CoV-2 encodes two overlapping polyproteins-pp1a and pp1ab-that are required for viral replication and transcription 3, 4.

Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.Ĭoronaviruses infect humans and other animals and cause a variety of highly prevalent and severe diseases, including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) 7. One of these compounds (ebselen) also exhibited promising antiviral activity in cell-based assays.

Six of these compounds inhibited M pro, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 μM. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds-including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds-as inhibitors of M pro. We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of M pro of SARS-CoV-2 in complex with this compound. This programme focused on identifying drug leads that target main protease (M pro) of SARS-CoV-2: M pro is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-2 5, 6.

Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019–2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19) 1, 2, 3, 4.

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