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Discovery of Potent Pyrazoline-Based Covalent SARS-CoV-2 Main Protease Inhibitors** |
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| Authors: | Patrick Moon Charlotte M Zammit Qian Shao Dustin Dovala Lydia Boike Nathaniel J Henning Mark Knapp Jessica N Spradlin Carl C Ward Helene Wolleb Daniel Fuller Gabrielle Blake Jason P Murphy Feng Wang Yipin Lu Stephanie A Moquin Laura Tandeske Matthew J Hesse Jeffrey M McKenna John A Tallarico Markus Schirle F Dean Toste Daniel K Nomura |
| Affiliation: | 1. Department of Chemistry, University of California, Berkeley, Berkeley, CA-94720 USA
Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA-94720 USA These authors contributed equally to this work.;2. Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA-94720 USA Novartis Institutes for BioMedical Research, Emeryville, CA 94608 USA These authors contributed equally to this work.;3. Department of Chemistry, University of California, Berkeley, Berkeley, CA-94720 USA Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA-94720 USA These authors contributed equally to this work.;4. Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA-94720 USA Novartis Institutes for BioMedical Research, Cambridge, MA 02139 USA;5. Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, CA-94720 USA Novartis Institutes for BioMedical Research, Emeryville, CA 94608 USA;6. Novartis Institutes for BioMedical Research, Emeryville, CA 94608 USA;7. Department of Chemistry, University of California, Berkeley, Berkeley, CA-94720 USA |
| Abstract: | While vaccines and antivirals are now being deployed for the current SARS-CoV-2 pandemic, we require additional antiviral therapeutics to not only effectively combat SARS-CoV-2 and its variants, but also future coronaviruses. All coronaviruses have relatively similar genomes that provide a potential exploitable opening to develop antiviral therapies that will be effective against all coronaviruses. Among the various genes and proteins encoded by all coronaviruses, one particularly “druggable” or relatively easy-to-drug target is the coronavirus Main Protease (3CLpro or Mpro), an enzyme that is involved in cleaving a long peptide translated by the viral genome into its individual protein components that are then assembled into the virus to enable viral replication in the cell. Inhibiting Mpro with a small-molecule antiviral would effectively stop the ability of the virus to replicate, providing therapeutic benefit. In this study, we have utilized activity-based protein profiling (ABPP)-based chemoproteomic approaches to discover and further optimize cysteine-reactive pyrazoline-based covalent inhibitors for the SARS-CoV-2 Mpro. Structure-guided medicinal chemistry and modular synthesis of di- and tri-substituted pyrazolines bearing either chloroacetamide or vinyl sulfonamide cysteine-reactive warheads enabled the expedient exploration of structure-activity relationships (SAR), yielding nanomolar potency inhibitors against Mpro from not only SARS-CoV-2, but across many other coronaviruses. Our studies highlight promising chemical scaffolds that may contribute to future pan-coronavirus inhibitors. |
| Keywords: | activity-based protein profiling chemoproteomics covalent ligand coronavirus Main Protease |