Discovery of a Novel Inhibitor of Coronavirus 3CL Protease as a Clinical Candidate for the Potential Treatment of COVID-19

Boras, B.; Jones, R. M.; Anson, B. J.; Arenson, D.; Aschenbrenner, L.; Bakowski, M. A.; Beutler, N.; Binder, J.; Chen, E.; Eng, H.; Hammond, J.; Hoffman, R.; Kadar, E. P.; Kania, R.; Kimoto, E.; Kirkpatrick, M. G.; Lanyon, L.; Lendy, E. K.; Lillis, J. R.; Luthra, S. A.; Ma, C.; Noell, S.; Obach, R. S.; O'Brien, M. N.; O'Connor, R.; Ogilvie, K.; Owen, D.; Pettersson, M.; Reese, M. R.; Rogers, T.; Rossulek, M. I.; Sathish, J. G.; Steppan, C.; Ticehurst, M.; Updyke, L. W.; Zhu, Y.; Wang, J.; Chatterjee, A. K.; Mesecar, A. D.; Anderson, A. S.; Allerton, C.

doi:10.1101/2020.09.12.293498

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bioRxiv · 10.1101/2020.09.12.293498

Discovery of a Novel Inhibitor of Coronavirus 3CL Protease as a Clinical Candidate for the Potential Treatment of COVID-19

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Abstract

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. The designed phosphate prodrug PF-07304814 is metabolized to PF-00835321 which is a potent inhibitor in vitro of the coronavirus family 3CL pro, with selectivity over human host protease targets. Furthermore, PF-00835231 exhibits potent in vitro antiviral activity against SARS-CoV-2 as a single agent and it is additive/synergistic in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of this compound as a potential COVID-19 treatment.

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Boras, B., Jones, R. M., Anson, B. J., Arenson, D., Aschenbrenner, L., Bakowski, M. A., Beutler, N., Binder, J., Chen, E., Eng, H., Hammond, J., Hoffman, R., Kadar, E. P., Kania, R., Kimoto, E., Kirkpatrick, M. G., Lanyon, L., Lendy, E. K., Lillis, J. R., Luthra, S. A., Ma, C., Noell, S., Obach, R. S., O'Brien, M. N., O'Connor, R., Ogilvie, K., Owen, D., Pettersson, M., Reese, M. R., Rogers, T., Rossulek, M. I., Sathish, J. G., Steppan, C., Ticehurst, M., Updyke, L. W., Zhu, Y., Wang, J., Chatterjee, A. K., Mesecar, A. D., Anderson, A. S., Allerton, C.. 2020-09-13. Discovery of a Novel Inhibitor of Coronavirus 3CL Protease as a Clinical Candidate for the Potential Treatment of COVID-19. https://doi.org/10.1101/2020.09.12.293498

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