Scientists determine first 3D structure of COVID-19 main protease

A team of Chinese scientists has reported the high-resolution crystal structure of the main protease (M^pro) of the COVID-19 virus and has identified drugs that may hold promise in combating the virus.

Prof. RAO Zihe and Prof. YANG Haitao from the Shanghai Institute for Advanced Immunochemical Studies of ShanghaiTech University, Prof. JIANG Hualiang from the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences and their collaborators conducted the research, which was published online in Nature on April 9.

M^pro, a key coronavirus enzyme, plays a pivotal role in mediating viral replication and transcription, making it an attractive antiviral drug target. To identify new drug leads for targeting M^pro in the COVID-19 virus, the researchers initiated a program of combined structure-assisted drug design, virtual drug screening and high-throughput screening.

Using computer-aided drug design, the researchers identified a mechanism-based inhibitor, N3, and subsequently determined the crystal structure of COVID-19 virus M^pro in complex with this compound on Jan. 26. The subsequent publication of this information represents the first 3D structure from the COVID-19 virus available in the public domain.

Using a combination of structure-based virtual and high-throughput screening, the scientists then assayed over 10,000 compounds, including approved drugs, drug candidates in clinical trials, and other pharmacologically active compounds, as potential inhibitors of M^pro. Among the compounds studied, six inhibited M^pro with IC50 values ranging from 0.67 to 21.4 μM. The compound ebselen also exhibited promising antiviral activity in cell-based assays.

In this study, the convergence of structure-based ab initio drug design, virtual screening and high-throughput screening was proved to be an efficient strategy for finding antiviral leads to combat the COVID-19 virus. The methods presented can greatly accelerate finding drug leads with clinical potential to fight new emerging infectious diseases that currently lack specific drugs and vaccines.

The team publicly released the list of candidate drugs on Jan. 25 and the structure of the COVID-19 virus M^pro on Jan. 26, in advance of officially releasing the results.

Before the M^pro structure was officially released on the Protein Data Bank (PDB), the team decided to provide its research data to over 300 research teams from academia to industry worldwide to help to accelerate the global research combating pandemic. By doing this, the team propelled research efforts around the world by helping clinicians, vaccine researchers and other professionals get a better understanding of the new virus.

In February, the crystal structure of COVID-19 virus M^pro (also known as 3CL protease) was selected as the February Molecule of the Month by PDB and was featured in PDB news. The PDB press release noted that the "rapid public release of this structure of the main protease of the virus (PDB 6lu7) will enable research on this newly recognized human pathogen."