Organocatalysis for the Treatment of Sickle Cell Disease.

描述（由申请人提供）：治疗镰状细胞病（SCD）的一种潜在治疗方法涉及给予含芳基甜菜碱的小分子，其与血红蛋白（HbS）形成席夫碱加合物并预防镰状化。这种方法的实用性是固有的限制，因为在生理条件下，芳基醛和HbS的1-氨基之间的席夫碱形成的动力学是动力学缓慢的。我们的方法利用良性有机催化剂来原位产生高反应性治疗剂（AIC），其以增强的速率与HbS反应。在初步研究中，仅添加ImM催化剂就显著增加了与Hb的席夫碱加合物形成，如通过氧亲和力的变化所测量的。我们假设该策略在临床上可用于降低疗效所需的治疗剂量，从而降低不良反应的可能性。拟议项目的两个具体目标是：（I）确定在溶液中和在SS红细胞中实现与游离Hb形成不同水平的加合物所需的醛和催化剂的最佳水平，（II）通过显微镜确定催化剂对离体红细胞镰状化和SS细胞形态的影响，并通过阳离子交换色谱确定催化剂对席夫碱加合物形成程度的影响。II期研究包括在缺氧条件下在小鼠镰状细胞模型中对催化剂疗效影响的体内评价、包括生物利用度在内的药代动力学研究以及任何不良反应的研究。我们计划将通过良性有机催化剂和芳香醛之间的反应形成的AIC商业化，作为治疗SCD的新型治疗剂。在第二阶段工作完成后，我们将与一家跨国制药公司合作，通过临床试验开发治疗药物。 公共卫生相关性：镰状细胞病（SCD）是一种遗传性疾病，造成超过75，000名美国人和1300万人在世界各地。该项目旨在促进有机催化剂的使用，以提供以较低临床剂量治疗镰状细胞病的改进疗法。

DESCRIPTION (provided by applicant): One potential therapeutic approach to treat sickle cell disease (SCD) involves the administration of aryl aldehyde-containing small molecules that form Schiff base adducts with hemoglobin (HbS) and prevent sickling. The utility of this approach is inherently limited as the kinetics of Schiff base formation between an aryl aldehyde and 1-amino group of HbS is kinetically slow under physiological conditions. Our approach utilizes benign organic catalysts to create a highly reactive therapeutic (AIC) in situ that reacts with HbS at enhanced rates. In preliminary studies, the addition of just 1 mM catalyst dramatically increased Schiff base adduct formation with Hb, as measured by the changes in oxygen affinity. We hypothesize that this strategy will be clinically useful in reducing the therapeutic doses required for efficacy, thus attenuating the likelihood of adverse effects The two Specific Aims of the proposed project are: (I) determination of the optimum levels of aldehyde and catalyst required to achieve different levels of adduct formation with free Hb in solution and in SS red blood cells, and (II) establish the effect of catalyst on the Ex vivo red blood cell sickling and morphology of SS cells by microscopy, and confirm the influence of catalyst on the degree of Schiff base adduct formation using cation exchange chromatography. Phase II efforts include in vivo evaluations of catalyst influence on efficacy in a murine sickle cell model under hypoxic conditions, pharmokinetic studies including bioavailability, and the study of any adverse effects. We plan to commercialize the AIC, formed by reaction between a benign organic catalyst and aromatic aldehyde, as a novel therapeutic for the treatment of SCD. After completion of Phase II efforts, we will partner with a multinational pharmaceutical company to develop the therapeutics through clinical trials. PUBLIC HEALTH RELEVANCE: Sickle cell disease (SCD) is a genetic disorder that inflicts over 75,000 Americans and 13 million people worldwide. This project seeks to advance the use of organic catalysts to provide for improved therapeutics that treat sickle cell disease at lower clinical doses.