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 (PLpro) 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 PLpro inhibitors have, to date, lacked the inhibitory potency and requisite pharmacokinetics to demonstrate that targeting PLpro 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 PLpro inhibitors, with lead compound PF-07957472 (4) providing robust efficacy in a mouse-adapted model of COVID-19 infection.
Subject(s)
Antiviral Agents , COVID-19 Drug Treatment , Coronavirus Papain-Like Proteases , Disease Models, Animal , SARS-CoV-2 , Animals , Mice , SARS-CoV-2/drug effects , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Coronavirus Papain-Like Proteases/metabolism , Humans , COVID-19/virology , Protease Inhibitors/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/therapeutic use , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/metabolism , Machine Learning , Female , Virus Replication/drug effectsABSTRACT
This work characterizes a previously undetected epimerization in the preparation of alkynyl diols from pentose precursors utilizing the Ohira-Bestmann reagent. Lithium trimethylsilyldiazomethane (Colvin reagent) additions to the d-ribose and d-lyxose-derived benzylidene acetals provide the respective alkynyl diol stereoisomers, without epimerization. Regioselective tungsten-catalyzed cycloisomerizations of the d-ribose- and d-lyxose-derived alkynyl diols yield rigid bicyclic pyranose glycals, confirming the stereochemical fidelity of the Colvin alkynylation process.