α-ketoamides have a ring coined the γ-lactam ring because it cleaves the peptide bond of the glutamate residue in the protease. These inhibitors with the γ-lactam ring have been shown to improve the protease inhibition properties by ten-fold. The side chains off of the P1’, P2, and P3 positions were changed for each the 11 inhibitors in this structural design based study. 
Additionally, this paper chose α-ketoamides as inhibitors because of the two hydrogen bonding acceptor locations, where other inhibitors, such as Michael acceptors and aldehydes, only have one. This allows for it to bind to the main protease better. 

Structure of α-ketoamides/reasoning for design  

A structure-based design study observed 11 different alpha-ketoamide protease inhibitors on the Nsp5, 3C- like main protease in coronaviruses and the 3C main protease in enteroviruses. These are the enzymes that are required for protein processing in viruses. 

Grand Valley State University

Coronavirus 3C-like proteases are the enzymes on the virus that play a key role in viral replication. Coronaviral protease inhibitors could theoretically prevent the virus from initially infecting the host cell, and appear to be promising drug targets. 

Types:
- GC376
- C-Phycoyanin
- peptidomimetic α-ketoamides 

Using Coronaviral Protease Inhibitors to Treat or Prevent COVID-19

Zhang, L., Lin, D., Kusov, Y., Nian, Y., Ma, Q., Wang, J., von Brunn, A., Leyssen, P., Lanko, K., Neyts, J., de Wilde, A., Snijder, E. J., Liu, H., & Hilgenfeld, R. (2020). α-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment. Journal of medicinal chemistry, 63(9), 4562–4578. https://doi.org/10.1021/acs.jmedchem.9b01828

α‑Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment 

Wang and colleagues used differential scanning fluorimetry to look at the binding affinity of GC376 and other main protease inhibitors to SARS-CoV-2.

Study Investigating the Effectiveness of GC376 as a Coronaviral Protease Inhibitor

Important Values to Define when Discussing Protease Inhibitors

An in-silico study was performed to assess the effectiveness of C-phycoyanin, a compound in spirulina, to inhibit nsp12, a molecule that is required for replication of SARS-CoV-2. 

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