Structure-based discovery of highly bioavailable, covalent, broad-spectrum coronavirus M<sup>Pro</sup> inhibitors with potent in vivo efficacy.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 40267184.
- Also identified by DOI 10.1126/sciadv.adt7836 and PMC identifier 12017303.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The main protease (M<sup>Pro</sup>) 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 M<sup>Pro</sup> inhibition >1000-fold by engaging additional M<sup>Pro</sup> subsites and using a latent electrophile to engage Cys<sup>145</sup>. Advanced leads from this series show pan-coronavirus antiviral activity, low clearance in mice, and for <b>AVI-4773</b>, 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 <b>AVI-4773</b>. <b>AVI-4516</b> shows minimal inhibition of major cytochrome P450s and human proteases. <b>AVI-4516</b> also exhibits synergy with the RNA-dependent RNA polymerase inhibitor, molnupiravir, in cellular infection models. Related analogs strongly inhibit nirmatrelvir-resistant M<sup>Pro</sup> mutant virus. The properties of this chemotype are differentiated from existing clinical and preclinical M<sup>Pro</sup> inhibitors and will advance therapeutic development against emerging SARS-CoV-2 variants and other coronaviruses.
Medical subject headings
- SARS-CoV-2
- Antiviral Agents
- COVID-19 Drug Treatment
- Coronavirus 3C Proteases
- Protease Inhibitors