Clear Creek Bio is developing brequinar, a potent oral inhibitor of dihydroorotate dehydrogenase (DHODH) as a clinical-stage, host-targeting, antiviral 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 antiviral activity against a wide range of medically relevant viruses.
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.