Pan-Coronavirus Protease Engagement and Differentiated Pharmacology of Antiviral Candidate CMX990
- 1Calibr-Skaggs Institute for Innovative Medicines, The Scripps Research Institute, La Jolla, CA, USA
Abstract
COVID-19 highlighted the need for antivirals that can be rapidly deployed against both current and future coronavirus threats. CMX990 is a clinical stage coronavirus main protease (Mpro) inhibitor bearing a unique trifluoromethoxymethyl ketone warhead. Here, we broadly evaluate its pan-coronavirus target engagement, antiviral breadth, and pharmacologic differentiation. Across a reporter panel of 24 Mpro enzymes spanning alpha-, beta-, delta-, and gamma-coronaviruses, CMX990 retained robust potent activity, including against nirmatrelvir-resistant SARS-CoV-2 variants. In direct comparison, nirmatrelvir and ensitrelvir showed diminished potency against non-SARS-CoV-2 coronaviruses. Live-virus assays corroborated this breadth, with potent, selective activity against SARS-CoV-2, SARS-CoV-1, MERS-CoV, and additional human coronaviruses. Structural studies revealed a conserved covalent binding mode centered on the catalytic Cys of coronavirus Mpro. In serial-passage studies, resistance emerged only after approximately twice as many serial passages under CMX990 selection as under nirmatrelvir selection, without selecting for the canonical nirmatrelvir-resistance substitution E166V. Extracellular washout experiments revealed superior persistence of antiviral activity relative to nirmatrelvir, consistent with durable target engagement. In a murine SARS-CoV-2 infection model, once-daily CMX990 protected against weight loss and reduced lung viral titers to near baseline levels. Collectively, these findings identify CMX990 as a structurally and functionally validated pan-coronavirus protease inhibitor supporting its potential as a pandemic-ready antiviral candidate.
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BibTeX
@misc{elshan2026pancoronavirus,
title = {{Pan-Coronavirus Protease Engagement and Differentiated Pharmacology of Antiviral Candidate CMX990}},
author = {N. G. R. D. Elshan and K. C. Wolff and L. Riva and M. A. Bakowski and S. Babarinde and A. Chaudhary and M. Zeller and A. K. Woods and G. Grabovyi and K. B. Wilson and R. A. Leonard and B. L. McGovern and J. Benjamin and I. Suazo and M. Gordon and F. O. Weiss and S. Ghorai and J. R. Pedroarena and K. L. Marquardt and M. Bimal and S. Weston and C. Dillen and A. M. Jadhav and M. G. Kirkpatrick and A. Gebara-Lamb and N. Farhat and V. T. B. Nguyen-Tran and V. Chi and K.-J. Lee and C. W. McNamara and A. K. Gupta and A. Rahimi and J. R. Teijaro and J. J. Chen and S. B. Joseph and M. Frieman and N. S. Heaton and K. White and I. A. Wilson and P. G. Schultz and S. K. Chanda and Chatt},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.29.755428},
url = {https://www.biorxiv.org/content/10.64898/2026.09.29.755428v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Pan-Coronavirus Protease Engagement and Differentiated Pharmacology of Antiviral Candidate CMX990
AU - N. G. R. D. Elshan
AU - K. C. Wolff
AU - L. Riva
AU - M. A. Bakowski
AU - S. Babarinde
AU - A. Chaudhary
AU - M. Zeller
AU - A. K. Woods
AU - G. Grabovyi
AU - K. B. Wilson
AU - R. A. Leonard
AU - B. L. McGovern
AU - J. Benjamin
AU - I. Suazo
AU - M. Gordon
AU - F. O. Weiss
AU - S. Ghorai
AU - J. R. Pedroarena
AU - K. L. Marquardt
AU - M. Bimal
AU - S. Weston
AU - C. Dillen
AU - A. M. Jadhav
AU - M. G. Kirkpatrick
AU - A. Gebara-Lamb
AU - N. Farhat
AU - V. T. B. Nguyen-Tran
AU - V. Chi
AU - K.-J. Lee
AU - C. W. McNamara
AU - A. K. Gupta
AU - A. Rahimi
AU - J. R. Teijaro
AU - J. J. Chen
AU - S. B. Joseph
AU - M. Frieman
AU - N. S. Heaton
AU - K. White
AU - I. A. Wilson
AU - P. G. Schultz
AU - S. K. Chanda
AU - Chatt
PY - 2026
DA - 2026/09/29
PB - bioRxiv
DO - 10.64898/2026.09.29.755428
UR - https://www.biorxiv.org/content/10.64898/2026.09.29.755428v1
AB - COVID-19 highlighted the need for antivirals that can be rapidly deployed against both current and future coronavirus threats. CMX990 is a clinical stage coronavirus main protease (Mpro) inhibitor bearing a unique trifluoromethoxymethyl ketone warhead. Here, we broadly evaluate its pan-coronavirus target engagement, antiviral breadth, and pharmacologic differentiation. Across a reporter panel of 24 Mpro enzymes spanning alpha-, beta-, delta-, and gamma-coronaviruses, CMX990 retained robust potent activity, including against nirmatrelvir-resistant SARS-CoV-2 variants. In direct comparison, nirmatrelvir and ensitrelvir showed diminished potency against non-SARS-CoV-2 coronaviruses. Live-virus assays corroborated this breadth, with potent, selective activity against SARS-CoV-2, SARS-CoV-1, MERS-CoV, and additional human coronaviruses. Structural studies revealed a conserved covalent binding mode centered on the catalytic Cys of coronavirus Mpro. In serial-passage studies, resistance emerged only after approximately twice as many serial passages under CMX990 selection as under nirmatrelvir selection, without selecting for the canonical nirmatrelvir-resistance substitution E166V. Extracellular washout experiments revealed superior persistence of antiviral activity relative to nirmatrelvir, consistent with durable target engagement. In a murine SARS-CoV-2 infection model, once-daily CMX990 protected against weight loss and reduced lung viral titers to near baseline levels. Collectively, these findings identify CMX990 as a structurally and functionally validated pan-coronavirus protease inhibitor supporting its potential as a pandemic-ready antiviral candidate.
ER -