Development of inhibitors of biliverdin reductase for toxic hyperbilirubinemia

高胆红素血症是新生儿的常见现象，是Crigler-Najjar综合征的定义特征。胆绿素还原酶-A（BVRA）的抑制被假设为一种机制，以减少胆红素的生产，而不影响血红素催化，导致胆绿素作为最终产品，迄今为止，没有药物已被报道，以有效地抑制胆绿素还原酶在体内。因此，该项目旨在鉴定和开发新的胆绿素还原酶活性抑制剂，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，合作项目团队开发了两种qHTS检测方法（一种基于吸光度，另一种利用黄递酶偶联读数），并对许多小分子文库进行了高通量筛选。初步命中目前正在进行确认，在第二次测定，配对计数器和正交测定。

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.