Pan-Coronavirus Protease Engagement and Differentiated Pharmacology of Antiviral Candidate CMX990
Year: 2026
Type: preprint
Abstract: 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 (M pro ) 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 M pro 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 M pro . 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.
Authors: N. G. R. Dayan Elshan, Karen C. Wolff, Laura Riva, Malina A. Bakowski, Simeon Babarinde, Anshul Chaudhary, Mark Zeller, Ashley K. Woods, Gennadii Grabovyi, Katy B. Wilson, Rebecca A. Leonard, Briana L. McGovern, Jared Benjamin, Isidora Suazo, Mary Gordon, Frank O. Weiss, Sourav Ghorai, James R. Pedroarena, Kristi L. Marquardt, Maheeka Bimal, Stuart Weston, Carly Dillen, Appaso M. Jadhav, Melanie G. Kirkpatrick, Amal Gebara-Lamb, Nisar Farhat, Vân T. B. Nguyen-Tran, Victor Chi, Kyoung-Jin Lee, Case W. McNamara, Anil Kumar Gupta, Alireza Rahimi, John R. Teijaro, Jian Jeffrey Chen, Sean B. Joseph, Matthew Frieman, Nicholas S. Heaton, Kris White, Ian A. Wilson, Peter G. Schultz, Sumit K. Chanda, Arnab K. Chatterjee
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7216225497