Development of inhibitors of biliverdin reductase for toxic hyperbilirubinemia

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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-coupled readout) and performed high-throughput screening against a number of small molecule libraries. Initial hits are currently undergoing confirmation in a secondary assay, paired with counter and orthogonal assays.