Discovery and Mechanism of SARS-CoV-2 Main Protease Inhibitors.
Sarah HuffIndrasena Reddy KummethaShashi Kant TiwariMatthew B HuanteAlex E ClarkShaobo WangWilliam BrayDavey SmithAaron F CarlinMark EndsleyTariq M RanaPublished in: Journal of medicinal chemistry (2021)
The emergence of a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents an urgent public health crisis. Without available targeted therapies, treatment options remain limited for COVID-19 patients. Using medicinal chemistry and rational drug design strategies, we identify a 2-phenyl-1,2-benzoselenazol-3-one class of compounds targeting the SARS-CoV-2 main protease (Mpro). FRET-based screening against recombinant SARS-CoV-2 Mpro identified six compounds that inhibit proteolysis with nanomolar IC50 values. Preincubation dilution experiments and molecular docking determined that the inhibition of SARS-CoV-2 Mpro can occur by either covalent or noncovalent mechanisms, and lead E04 was determined to inhibit Mpro competitively. Lead E24 inhibited viral replication with a nanomolar EC50 value (844 nM) in SARS-CoV-2-infected Vero E6 cells and was further confirmed to impair SARS-CoV-2 replication in human lung epithelial cells and human-induced pluripotent stem cell-derived 3D lung organoids. Altogether, these studies provide a structural framework and mechanism of Mpro inhibition that should facilitate the design of future COVID-19 treatments.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- public health
- molecular docking
- endothelial cells
- photodynamic therapy
- coronavirus disease
- induced apoptosis
- small molecule
- emergency department
- oxidative stress
- high throughput
- signaling pathway
- high resolution
- endoplasmic reticulum stress
- single cell
- case control
- quantum dots
- stress induced
- diabetic rats
- cell free