Development of inhibitors of biliverdin reductase for toxic hyperbilirubinemia

高胆红素血症是新生儿的常见现象，也是Crigler-Najjar综合征的典型特征。抑制胆绿素还原酶-A(BVRA)被认为是一种在不影响血红素分解代谢的情况下减少胆红素产生的机制，导致胆绿素作为最终产物，到目前为止还没有药物在体内有效地抑制胆绿素还原酶。因此，本项目旨在寻找和开发体内胆绿素还原酶活性的新型抑制剂，以将血清胆红素降低到安全水平，并减轻胆红素诱导的神经功能障碍(BIND)。 在此期间，合作项目组开发了两种qHTS分析方法(一种基于吸光度，另一种使用黄递酶偶联读数)，并对一些小分子文库进行了高通量筛选。最初的命中目前正在进行二次化验，与计数器和正交分析配对。

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.