Development of inhibitors of biliverdin reductase for toxic hyperbilirubinemia

National Center For Advancing Translational Sciences

Investigators

Abstract

Hyperbilirubinemia is a common phenomenon in newborns, and is a defining characteristic of Crigler-Najjar syndrome. Inhibition of biliverdin reductase-A (BVRA) has been hypothesized as a mechanism to reduce bilirubin production without affecting heme catabolism, resulting in biliverdin as the end product, and to date no drug has been reported to effectively inhibit biliverdin reductase in vivo. As such this project aims to identify and develop novel inhibitors of biliverdin reductase activity in vivo to reduce serum bilirubin to safe levels and mitigate bilirubin-induced neural dysfunction (BIND). During this period, the collaborative project team has developed two qHTS assays (one absorbance-based and one utilizing a diaphorase-coupling readout) and performed high-throughput screening against a large collection of small molecules. Initial hits are in the process of being cherrypicked and confirmed in a secondary assay, paired with counter and orthogonal assays.