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)1-4. Currently, there are no targeted therapeutic
agents for the treatment of this disease, and effective treatment options remain very
limited. 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. This programme focused on identifying
drug leads that target main protease (Mpro) of SARS-CoV-2: Mpro 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-25,6. We identified a mechanism-based
inhibitor (N3) by computer-aided drug design, and then determined the crystal structure
of Mpro of SARS-CoV-2 in complex with this compound. 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 Mpro. Six of these compounds inhibited Mpro, showing half-maximal
inhibitory concentration values that ranged from 0.67 to 21.4 μM. One of these compounds
(ebselen) also exhibited promising antiviral activity in cell-based assays. 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.