Quantitative prediction of erythrocyte sickling for the development of advanced sickle cell therapies
Quantitative prediction of erythrocyte sickling for the development of advanced sickle cell therapies
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DOI：
10.1126/sciadv.aax3905
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发表时间：
2019-08-01
期刊：
影响因子：
13.6
通讯作者：
Karniadakis, George Em
中科院分区：
文献类型：
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作者：
Lu, Lu;Li, Zhen;Karniadakis, George Em
镰状细胞病是由正常成人血红蛋白转化为镰状血红蛋白（HbS）并引起脱氧HbS和红细胞镰状化的细胞内聚合的突变引起的。抗镰状化疗法的发展需要定量了解器官特异性条件下的HbS聚合动力学，这难以用现有的实验技术进行评估。因此，我们开发了一个基于经典成核理论的动力学模型来研究潜在的抗镰状化候选药物的有效性。我们通过比较其预测性与先前的体内和体外实验结果来验证该模型。我们使用该模型来量化镰状化抑制剂的疗效，并获得与最近的筛选试验一致的结果。在模型中的动力学参数的全局灵敏度分析表明，溶解度，成核速率前因子，和氧亲和力的量，决定HbS聚合。这一发现为镰状化抑制剂靶向细胞内过程的发现提供了定量指导。
Sickle cell disease is induced by a mutation that converts normal adult hemoglobin to sickle hemoglobin (HbS) and engenders intracellular polymerization of deoxy-HbS and erythrocyte sickling. Development of anti-sickling therapies requires quantitative understanding of HbS polymerization kinetics under organ-specific conditions, which are difficult to assess with existing experimental techniques. Thus, we developed a kinetic model based on the classical nucleation theory to examine the effectiveness of potential anti-sickling drug candidates. We validated this model by comparing its predictability against prior in vivo and in vitro experimental results. We used the model to quantify the efficacy of sickling inhibitors and obtain results consistent with recent screening assays. Global sensitivity analysis on the kinetic parameters in the model revealed that the solubility, nucleation rate prefactor, and oxygen affinity are quantities that dictate HbS polymerization. This finding provides quantitative guidelines for the discovery of intracellular processes to be targeted by sickling inhibitors.