Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19

Britton Boras; Rhys M. Jones; Brandon J. Anson; Dan Arenson; Lisa Aschenbrenner; Malina A. Bakowski; Nathan Beutler; Joseph Binder; Emily Chen; Heather Eng; Holly Hammond; Jennifer Hammond; Robert E. Haupt; Robert Hoffman; Eugene P. Kadar; Rob Kania; Emi Kimoto; Melanie G. Kirkpatrick; Lorraine Lanyon; Emma K. Lendy; Jonathan R. Lillis; James Logue; Suman A. Luthra; Chunlong Ma; Stephen W. Mason; Marisa E. McGrath; Stephen Noell; R. Scott Obach; Matthew N. O’ Brien; Rebecca O’Connor; Kevin Ogilvie; Dafydd Owen; Martin Pettersson; Matthew R. Reese; Thomas F. Rogers; Romel Rosales; Michelle I. Rossulek; Jean G. Sathish; Norimitsu Shirai; Claire Steppan; Martyn Ticehurst; Lawrence W. Updyke; Stuart Weston; Yuao Zhu; Kris M. White; Adolfo García-Sastre; Jun Wang; Arnab K. Chatterjee; Andrew D. Mesecar; Matthew B. Frieman; Annaliesa S. Anderson; Charlotte Allerton

doi:10.1038/s41467-021-26239-2

Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19

Britton Boras, Rhys M. Jones, Brandon J. Anson, Dan Arenson, Lisa Aschenbrenner, Malina A. Bakowski, Nathan Beutler, Joseph Binder, Emily Chen, Heather Eng, Holly Hammond, Jennifer Hammond, Robert E. Haupt, Robert Hoffman, Eugene P. Kadar, Rob Kania, Emi Kimoto, Melanie G. Kirkpatrick, Lorraine Lanyon, Emma K. LendyJonathan R. Lillis, James Logue, Suman A. Luthra, Chunlong Ma, Stephen W. Mason, Marisa E. McGrath, Stephen Noell, R. Scott Obach, Matthew N. O’ Brien, Rebecca O’Connor, Kevin Ogilvie, Dafydd Owen, Martin Pettersson, Matthew R. Reese, Thomas F. Rogers, Romel Rosales, Michelle I. Rossulek, Jean G. Sathish, Norimitsu Shirai, Claire Steppan, Martyn Ticehurst, Lawrence W. Updyke, Stuart Weston, Yuao Zhu, Kris M. White, Adolfo García-Sastre, Jun Wang, Arnab K. Chatterjee, Andrew D. Mesecar, Matthew B. Frieman, Annaliesa S. Anderson, Charlotte Allerton

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213 Scopus citations

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. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.

Original language	English (US)
Article number	6055
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-26239-2
State	Published - Dec 1 2021

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-021-26239-2

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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, H., Hammond, J., Haupt, R. E., Hoffman, R., Kadar, E. P., Kania, R., Kimoto, E., Kirkpatrick, M. G., Lanyon, L., ... Allerton, C. (2021). Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19. Nature communications, 12(1), Article 6055. https://doi.org/10.1038/s41467-021-26239-2

Boras, B, Jones, RM, Anson, BJ, Arenson, D, Aschenbrenner, L, Bakowski, MA, Beutler, N, Binder, J, Chen, E, Eng, H, Hammond, H, Hammond, J, Haupt, RE, Hoffman, R, Kadar, EP, Kania, R, Kimoto, E, Kirkpatrick, MG, Lanyon, L, Lendy, EK, Lillis, JR, Logue, J, Luthra, SA, Ma, C, Mason, SW, McGrath, ME, Noell, S, Obach, RS, O’ Brien, MN, O’Connor, R, Ogilvie, K, Owen, D, Pettersson, M, Reese, MR, Rogers, TF, Rosales, R, Rossulek, MI, Sathish, JG, Shirai, N, Steppan, C, Ticehurst, M, Updyke, LW, Weston, S, Zhu, Y, White, KM, García-Sastre, A, Wang, J, Chatterjee, AK, Mesecar, AD, Frieman, MB, Anderson, AS & Allerton, C 2021, 'Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19', Nature communications, vol. 12, no. 1, 6055. https://doi.org/10.1038/s41467-021-26239-2

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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. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.",

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AU - Aschenbrenner, Lisa

AU - Bakowski, Malina A.

AU - Beutler, Nathan

AU - Binder, Joseph

AU - Chen, Emily

AU - Eng, Heather

AU - Hammond, Holly

AU - Hammond, Jennifer

AU - Haupt, Robert E.

AU - Hoffman, Robert

AU - Kadar, Eugene P.

AU - Kania, Rob

AU - Kimoto, Emi

AU - Kirkpatrick, Melanie G.

AU - Lanyon, Lorraine

AU - Lendy, Emma K.

AU - Lillis, Jonathan R.

AU - Logue, James

AU - Luthra, Suman A.

AU - Ma, Chunlong

AU - Mason, Stephen W.

AU - McGrath, Marisa E.

AU - Noell, Stephen

AU - Obach, R. Scott

AU - O’ Brien, Matthew N.

AU - O’Connor, Rebecca

AU - Ogilvie, Kevin

AU - Owen, Dafydd

AU - Pettersson, Martin

AU - Reese, Matthew R.

AU - Rogers, Thomas F.

AU - Rosales, Romel

AU - Rossulek, Michelle I.

AU - Sathish, Jean G.

AU - Shirai, Norimitsu

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AU - Ticehurst, Martyn

AU - Updyke, Lawrence W.

AU - Weston, Stuart

AU - Zhu, Yuao

AU - White, Kris M.

AU - García-Sastre, Adolfo

AU - Wang, Jun

AU - Chatterjee, Arnab K.

AU - Mesecar, Andrew D.

AU - Frieman, Matthew B.

AU - Anderson, Annaliesa S.

AU - Allerton, Charlotte

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Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19

Abstract

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