Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 38547259.
- Also identified by DOI 10.1126/science.adm9724 and PMC identifier 12178660.
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Abstract
The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. The SARS-CoV-2 papain-like protease (PL<sup>pro</sup>) is a promising but challenging drug target. We designed and synthesized 85 noncovalent PL<sup>pro</sup> inhibitors that bind to a recently discovered ubiquitin binding site and the known BL2 groove pocket near the S4 subsite. Leads inhibited PL<sup>pro</sup> with the inhibitory constant K<sub>i</sub> values from 13.2 to 88.2 nanomolar. The co-crystal structures of PL<sup>pro</sup> with eight leads revealed their interaction modes. The in vivo lead Jun12682 inhibited SARS-CoV-2 and its variants, including nirmatrelvir-resistant strains with EC<sub>50</sub> from 0.44 to 2.02 micromolar. Oral treatment with Jun12682 improved survival and reduced lung viral loads and lesions in a SARS-CoV-2 infection mouse model, suggesting that PL<sup>pro</sup> inhibitors are promising oral SARS-CoV-2 antiviral candidates.
Medical subject headings
- Coronavirus Papain-Like Proteases
- COVID-19
- SARS-CoV-2
- Coronavirus Protease Inhibitors
- Drug Design
- COVID-19 Drug Treatment