How can the structral characteristics of the SARS-CoV-2 main protease be used for the design of an antiviral inhibitor?

Bottom Line:

A candidate drug for antiviral therapy (α-ketoamide inhibitors) has been designed by studying the structure of the main protease of SARS-CoV-2, and can be administered by inhalation.

Reference:

Zhang, L. et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science (2020). DOI: https://doi.org/10.1126/science.abb3405

Date Published:

20 March 2020

Synopsis:

During the SARS-CoV-2 infection of human cells, it uses cell machinery to produce proteins for its own replication. The SARS-CoV-2 virus has a main protease, or protein-cutting enzyme, which is essential for its processing of proteins translated from viral RNA. Blocking this enzyme with a small molecule inhibitor, such as an α-ketoamide, would therefore stop viral replication and potentially serve as a useful treatment modality in patients with COVID-19. The authors began with a lead compound previously identified to be a broad-spectrum inhibitor of the main proteases of beta- and alpha-coronarviruses, and made various structural modifications that increased its stability and solubility in plasma, decreased its affinity to plasma proteins, and had the best “fit” with the active site of the main protease (based on the crystal structure of the enzyme). In the authors’ studies of the absorption – distribution – metabolism – excretion (ADME) properties of their proposed inhibitor, they found that their proposed inhibitor stayed in the blood plasma of mice for 2.7 hours on average and possibly had greater affinity for the lung tissue, which would be beneficial given that COVID-19 primarily targets the lungs in humans. Hence, in this paper, the authors proposed a small molecule inhibitor of the main protease of SARS-CoV-2 based on refinements to previously-identified broad-spectrum inhibitors that would optimize its potential pharmaceutical efficacy in COVID-19 patients.

Summary by: Mike Ge