| Title: |
Structure-based discovery of highly bioavailable, covalent, broad-spectrum coronavirus MPro inhibitors with potent in vivo efficacy |
| Authors: |
Detomasi, Tyler C; Degotte, Gilles; Huang, Sijie; Suryawanshi, Rahul K; Diallo, Amy; Lizzadro, Luca; Zapatero-Belinchón, Francisco J; Taha, Taha Y; Li, Jiapeng; Richards, Alicia L; Hantz, Eric R; Alam, Zain; Montano, Mauricio; McCavitt-Malvido, Maria; Gumpena, Rajesh; Partridge, James R; Correy, Galen J; Matsui, Yusuke; Charvat, Annemarie F; Glenn, Isabella S; Rosecrans, Julia; Revalde, Jezrael L; Anderson, Dashiell; Hultquist, Judd F; Arkin, Michelle R; Neitz, R Jeffrey; Swaney, Danielle L; Krogan, Nevan J; Shoichet, Brian K; Verba, Kliment A; Ott, Melanie; Renslo, Adam R; Craik, Charles S |
| Source: |
Science Advances, vol 11, iss 17 |
| Publisher Information: |
eScholarship, University of California |
| Publication Year: |
2025 |
| Collection: |
University of California: eScholarship |
| Subject Terms: |
3207 Medical Microbiology (for-2020); 32 Biomedical and Clinical Sciences (for-2020); Coronaviruses Therapeutics and Interventions (rcdc); Coronaviruses (rcdc); Biodefense (rcdc); Emerging Infectious Diseases (rcdc); Infectious Diseases (rcdc); 5.1 Pharmaceuticals (hrcs-rac); 3 Good Health and Well Being (sdg); Animals (mesh); SARS-CoV-2 (mesh); Mice (mesh); Humans (mesh); Antiviral Agents (mesh); COVID-19 Drug Treatment (mesh); Coronavirus 3C Proteases (mesh); Drug Discovery (mesh); Protease Inhibitors (mesh); Molecular Docking Simulation (mesh); COVID-19 (mesh); Hydroxylamines (mesh); Cytidine (mesh); Lactams (mesh); Leucine (mesh); Nitriles (mesh); Proline (mesh) |
| Time: |
eadt7836 |
| Description: |
The main protease (MPro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a validated drug target. Starting with a lead-like dihydrouracil chemotype identified in a large-library docking campaign, we improved MPro inhibition >1000-fold by engaging additional MPro subsites and using a latent electrophile to engage Cys145. Advanced leads from this series show pan-coronavirus antiviral activity, low clearance in mice, and for AVI-4773, a rapid reduction in viral titers >1,000,000 after just three doses. Both compounds are well distributed in mouse tissues, including brain, where concentrations >1000× the 90% effective concentration are observed 8 hours after oral dosing for AVI-4773. AVI-4516 shows minimal inhibition of major cytochrome P450s and human proteases. AVI-4516 also exhibits synergy with the RNA-dependent RNA polymerase inhibitor, molnupiravir, in cellular infection models. Related analogs strongly inhibit nirmatrelvir-resistant MPro mutant virus. The properties of this chemotype are differentiated from existing clinical and preclinical MPro inhibitors and will advance therapeutic development against emerging SARS-CoV-2 variants and other coronaviruses. |
| Document Type: |
article in journal/newspaper |
| Language: |
unknown |
| Relation: |
qt8qx6w7nt; https://escholarship.org/uc/item/8qx6w7nt |
| DOI: |
10.1126/sciadv.adt7836 |
| Availability: |
https://escholarship.org/uc/item/8qx6w7nt; https://doi.org/10.1126/sciadv.adt7836 |
| Rights: |
public |
| Accession Number: |
edsbas.8C0BAF02 |
| Database: |
BASE |