Discovery of SARS-CoV-2 papain-like protease (PL<sup>pro</sup>) inhibitors with efficacy in a murine infection model.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 39213347.
- Also identified by DOI 10.1126/sciadv.ado4288 and PMC identifier 11364104.
- 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
Vaccines and first-generation antiviral therapeutics have provided important protection against COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy and protection against potential viral resistance. The SARS-CoV-2 papain-like protease (PL<sup>pro</sup>) is one of the two essential cysteine proteases involved in viral replication. While inhibitors of the SARS-CoV-2 main protease have demonstrated clinical efficacy, known PL<sup>pro</sup> inhibitors have, to date, lacked the inhibitory potency and requisite pharmacokinetics to demonstrate that targeting PL<sup>pro</sup> translates to in vivo efficacy in a preclinical setting. Here, we report the machine learning-driven discovery of potent, selective, and orally available SARS-CoV-2 PL<sup>pro</sup> inhibitors, with lead compound PF-07957472 (<b>4</b>) providing robust efficacy in a mouse-adapted model of COVID-19 infection.
Medical subject headings
- SARS-CoV-2
- COVID-19 Drug Treatment
- Antiviral Agents
- Disease Models, Animal
- Coronavirus Papain-Like Proteases