Abstract
The main protease (3CL Mpro) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, is an essential enzyme for viral replication with no human counterpart, making it an attractive drug target. To date, no small-molecule clinical drugs are available that specifically inhibit SARS-CoV-2 Mpro. To aid rational drug design, we determined a neutron structure of Mpro in complex with the α-ketoamide inhibitor telaprevir at near-physiological (22 °C) temperature. We directly observed protonation states in the inhibitor complex and compared them with those in the ligand-free Mpro, revealing modulation of the active-site protonation states upon telaprevir binding. We suggest that binding of other α-ketoamide covalent inhibitors can lead to the same protonation state changes in the Mpro active site. Thus, by studying the protonation state changes induced by inhibitors, we provide crucial insights to help guide rational drug design, allowing precise tailoring of inhibitors to manipulate the electrostatic environment of SARS-CoV-2 Mpro.
| Original language | English |
|---|---|
| Pages (from-to) | 4991-5000 |
| Number of pages | 10 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 64 |
| Issue number | 8 |
| DOIs | |
| State | Published - Apr 22 2021 |
Funding
This research was supported by the DOE Office of Science through the National Virtual Biotechnology Laboratory (NVBL), a consortium of DOE national laboratories focused on response to COVID-19, with funding provided by the Coronavirus CARES Act. This research used resources at the SNS and the HFIR, which are DOE Office of Science User Facilities operated by the Oak Ridge National Laboratory (ORNL). The Office of Biological and Environmental Research supported research at ORNL’s Center for Structural Molecular Biology (CSMB), a DOE Office of Science User Facility. This research used resources of the Spallation Neutron Source Second Target Station Project at ORNL. ORNL is managed by UT-Battelle LLC for DOE’s Office of Science, the single largest supporter of basic research in the physical sciences in the United States. L.C. acknowledges support by the NIH (R01-GM071939). We thank Dr. Hugh M. O’Neill from ORNL for assistance during expression of the partially deuterated protein.
