Fluorescence Lifetime Measurement of Prefibrillar Sickle Hemoglobin Oligomers as a Platform for Drug Discovery in Sickle Cell Disease.
Fluorescence Lifetime Measurement of Prefibrillar Sickle Hemoglobin Oligomers as a Platform for Drug Discovery in Sickle Cell Disease.
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DOI：
10.1021/acs.biomac.2c00671
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发表时间：
2022-09-12
影响因子：
6.2
通讯作者：
Wood, David K.
中科院分区：
文献类型：
--
作者：
Vunnam, Nagamani;Hansen, Scott;Been, MaryJane Olivia;Lo, Chih Hung;Pandey, Anil K.;Paulsen, Carolyn N.;Rohde, John A.;Thomas, David D.;Sachs, Jonathan N.;Wood, David K.
自1949年以来，镰状细胞病（SCD）的分子起源就已为人所知，但治疗方法仍然有限。我们提出了第一个高通量筛选（HTS）平台，用于发现直接抑制镰状血红蛋白（HbS）寡聚化和改善血流的小分子，可能克服SCD药物发现的长期瓶颈。我们发现，在远低于成核和快速聚合阈值的浓度下，脱氧HbS形成多个α2β2四聚体的小组装体。我们的HTS平台利用高灵敏度的荧光寿命测量，监测这些时间稳定的前原纤维状HbS低聚物。我们表明，这种方法是敏感的化合物，抑制HbS聚合或不调节血红蛋白氧结合亲和力。我们还报告了中试小分子筛选的结果，其中我们发现并验证了几种新型的HbS寡聚化抑制剂。
The molecular origin of sickle cell disease (SCD) has been known since 1949, but treatments remain limited. We present the first high-throughput screening (HTS) platform for discovering small molecules that directly inhibit sickle hemoglobin (HbS) oligomerization and improve blood flow, potentially overcoming a long-standing bottleneck in SCD drug discovery. We show that at concentrations far below the threshold for nucleation and rapid polymerization, deoxygenated HbS forms small assemblies of multiple α2β2 tetramers. Our HTS platform leverages high-sensitivity fluorescence lifetime measurements that monitor these temporally stable prefibrillar HbS oligomers. We show that this approach is sensitive to compounds that inhibit HbS polymerization with or without modulating hemoglobin oxygen binding affinity. We also report the results of a pilot small-molecule screen in which we discovered and validated several novel inhibitors of HbS oligomerization.
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