A New Paradigm for Iron Replacement Therapy

项目概要/摘要 贫血影响了世界上约25%的人口，并导致不良后果。几种形式的贫血， 包括炎症性贫血（AI）和铁难治性缺铁性贫血（IRIDA），部分原因是 病理性铁（Fe）限制。在这些条件下，慢性免疫激活或基因突变上调 铁调节激素铁调素，铁调素反过来抑制膜铁转运蛋白的活性，膜铁转运蛋白是唯一已知的铁输出蛋白。 因此，铁调素过量导致严重形式的低铁血症，因为铁通过血红蛋白再循环释放， 巨噬细胞、肠细胞吸收的营养铁和其他储存的铁不能输出到血浆中 铁载体蛋白转铁蛋白分布。 铁调素过量患者的铁替代可能具有挑战性。大多数静脉内铁替代药物 是铁-碳水化合物纳米颗粒，在巨噬细胞中积累和代谢，需要膜铁转运蛋白 用于Fe动员。因此，静脉替代治疗对贫血纠正的疗效有限， 可能导致巨噬细胞中的Fe过载。铁调素驱动的铁限制也限制了铁的功效。 营养铁补充剂。没有临床上可用的铁调素调节药物。红细胞生成刺激 药物（ESA）可能为某些患者提供治疗益处，但与心血管毒性相关， 血栓形成和恶性肿瘤。 另一种方法是通过不依赖于膜铁转运蛋白的机制将Fe直接递送至转铁蛋白。一个 包含将Fe直接释放至转铁蛋白的焦磷酸柠檬酸铁（FPC）的静脉内制剂具有 FDA批准在血液透析期间使用。但是，必须注意确保血清FPC 浓度不超过血清总铁结合能力，因为暴露于有毒不稳定铁的情况发生在此之上 阈值为了安全地施用治疗上有意义的量的Fe，FPC在数小时内缓慢输注。 对于通过非依赖于铁转运蛋白的铁转运蛋白有效且安全地补充Fe的药物仍然存在未满足的需求。 途径。我们认为，一个高效的直接转铁蛋白铁替代药物可以开发，通过 配位化学原理的合理应用。在这里，我们提出药物设计的基础上， 前瞻性定义的分子特性。初步的体外和体内数据支持我们的方法是 使用我们合成的络合物Fe-BBG（BBG = N，N-（双）-2-羟基苄基-L-谷氨酸）提供， 我们最初的药物原型我们将反复合成和筛选一个有效性和安全性的复合物库 信号.有前途的候选人将被推进，以证明治疗效果的海葵纠正， IRIDA和慢性肾病的啮齿动物模型。此工作的输出将是一个或多个已消除风险的 作为直接转铁蛋白Fe替代药物的开发候选物。

Project Summary/ Abstract Anemia impacts ~25% of the world’s population and contributes to adverse outcomes. Several forms of anemia, including anemia of inflammation (AI) and iron-refractory iron deficiency anemia (IRIDA) are caused in part by pathologic iron (Fe) restriction. In these conditions, chronic immune activation or genetic mutations upregulate the Fe regulating hormone hepcidin, which in turn inhibits activity of ferroportin, the only known Fe exporter. Hepcidin excess thus imposes a severe form of hypoferremia as Fe liberated via hemoglobin recycling in macrophages, nutritional iron absorbed by enterocytes, and other stored Fe cannot be exported to the plasma iron-carrier protein transferrin for distribution. Fe replacement in patients with hepcidin excess can be challenging. Most intravenous Fe replacement drugs are Fe-carbohydrate nanoparticles that are accumulated and metabolized in macrophages, requiring ferroportin for Fe mobilization. Thus, iv replacement can simultaneously have limited efficacy for anemia correction while potentially contributing to Fe overload in macrophages. Hepcidin-driven Fe restriction also limits the efficacy of nutritional Fe supplements. There is no clinically available hepcidin-modulating drug. Erythropoiesis stimulating agents (ESA) may offer a therapeutic benefit for some patients, but are associated with cardiovascular toxicity, thrombosis, and malignancy in some studies. An alternate approach is to deliver Fe directly to transferrin via mechanisms independent of ferroportin. An intravenous formulation comprising iron pyrophosphate citrate (FPC) that releases Fe directly to transferrin has FDA approval for use during hemodialysis. However, care must be taken to ensure that serum FPC concentrations do not exceed serum total Fe binding capacity, as exposure to toxic labile Fe occurs above this threshold. To safely administer therapeutically meaningful quantities of Fe, FPC is slowly infused over hours. There remains an unmet need for drugs to efficiently and safely replenish Fe via ferroportin-independent pathways. We posit that a highly effective direct-to-transferrin Fe replacement drug can be developed through the judicious application of coordination chemistry principals. Here, we propose drug design based on a set prospectively defined molecular properties. Preliminary in vitro and in vivo data in support of our approach is provided using the complex Fe-BBG (BBG = N,N-(bis)-2-hydroxybenzyl-L-glutamic acid) that we synthesized as our initial drug prototype. We will iteratively synthesize and screen a library of complexes for efficacy and safety signals. Promising candidates will be advanced to demonstrate therapeutic efficacy for anemai correction in rodent models of IRIDA and chronic kidney disease. The output of this work will be one or more de-risked candidates for development as direct-to-transferrin Fe replacement drugs.