Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors

Zhang L, Lin D, Sun X, et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science. 2020;368(6489):409‐412. doi:10.1126/science.abb3405

Review written by:

Daniel Roybal, Henry Zhou, edited by Eunice Lee

Green - Critical biochemical analysis of one of the enzymes of SARS-Cov-2 and one possible therapeutic target.

One of the most well-characterized drug targets among all coronaviruses, including SARS-CoV-2, is the main protease Mpro, an essential enzyme for processing viral proteins. In February 2020, Zhang et al. created α-ketoamides targeted against the main proteases of different coronaviruses and enteroviruses.

Zhang et al. modified one of their previously established α-ketoamides, Compound 11r, in order to improve half-life within plasma and increase solubility. This led to three novel variants of α-ketoamide inhibitors, 13a, 13b, and 14b. Of note, 11r and 13a were designed as broad-spectrum inhibitors of both alpha and betacoronaviruses, as well as enteroviruses, whereas 13b and 14b more specifically target the SARS-CoV-2 Mpro. The authors then test each compound’s ability to inhibit the SARS-CoV-2 Mpro in vitro, followed by testing their pharmacokinetic properties in vivo in mice. The authors also identified the three-dimensional crystal structure of SARS-CoV-2 Mpro in order to test its interactions with each of the three compounds in silico.

Of the three compounds, 13b emerged as the compound with the most favorable pharmacokinetic profile and inhibitory activity, able to inhibit purified recombinant SARS-CoV-2 Mpro with IC50 = 0.67 ± 0.18 μM. 13b was also able to inhibit SARS-CoV-2 replication in human Calu-3 lung cells. Furthermore, 13b demonstrated lung tropism in mice in vivo, supporting its potential use as a therapeutic for COVID-19. 13a also demonstrated lung tropism--in fact, it showed greater lung retention than 13b--but showed reduced inhibitory activity compared to 13b and the original 11r compound. 14b showed no inhibitory activity and therefore was discarded.

Review Notes
  1. Although the authors brought Compound 13a and 13b to an in vivo mouse model to assess ADME properties, it is too early to extrapolate these findings to humans.

  2. While no adverse effects were observed after direct inhalation of the drug by mice, (suggesting a future route of administration to better target drug delivery to lung parenchyma), clinical trials are required to support safety claims.

  3. Given that recent studies have hinted at the nature of SARS-Cov-2’s neuroinvasive potential, and thus its potential for systemic invasion, it still remains to be seen whether Compound 13’s lung tropism will ultimately prove beneficial or detrimental to use in a clinical setting.

  4. Very primitive stage α-ketoamide inhibitors that should be tested in “in vivo” experiments. Preferently, monkeys with developing a COVID-19. ACE2 of rodents is quite different to human ones according to some papers.

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