Clear Creek Bio is developing brequinar, a potent oral inhibitor of dihydroorotate dehydrogenase (DHODH) as a clinical-stage drug candidate. Brequinar blocks de novo pyrimidine biosynthesis, a pathway involved in DNA and RNA metabolism. In vitro and in vivo studies have shown that brequinar has potent activity.
PLpro inhibitors have the potential to be unique and effective COVID-19 therapeutics that directly block viral replication and simultaneously enhance antiviral immunity.
PLpro is a SARS-CoV-2 enzyme whose catalytic activity is essential to fully process the viral polyprotein and assemble a functional replicase complex.
In addition to this critical role in viral replication, PLpro is a unique viral protease that cleaves important host regulators of innate immunity such as ISG15, resulting in dampened antiviral immune mechanisms.