Hepcidin Mimetics for the Treatment of Iron Overload Diseases

摘要 该SBIR I期的目标是开发用于治疗各种铁过载疾病的新疗法， 涉及使用hepcidin模拟物，并确定有效的研究性新药（IND）候选药物， 在地中海贫血疾病模型中的作用。有两种主要疾病，血色病和β-tha- 贫血，其特征在于铁过载。在这两种疾病中，低铁调素水平增加肠铁 吸收并增加网状内皮系统中回收铁的释放，从而导致铁的消耗 巨噬细胞铁，血清铁蛋白水平相对较低，肝脏铁浓度增加，并释放到 导致目标器官损伤的游离铁的循环。如果不治疗，铁会继续积累， 并且相当大比例的患者最终达到毒性铁超负荷水平。患者接受以下治疗 静脉切开术、输血和/或铁螯合剂，取决于疾病。螯合疗法与 具有相当大的毒性，目前现有的螯合剂用于治疗铁过载，缺乏显著的患者 依从性或与毒性、肾损害、肝损害和胃肠道出血相关- 出血。因此，非常需要更安全和更好耐受的新治疗方法。因为铁调素 由于具有复杂的4-二硫键结构，铁调素模拟物已被提出作为潜在的治疗剂。敬过度- 由于铁调素的物理化学限制，更有效、稳定、可溶和有效的替代支架 通过使用有目的地构建的基于结构的药物环境（Vecidin ™）来工程化铁调素。一 先导化合物（PN-8518）是在优化和分析由Vec鉴定的工程支架后鉴定的， Escort ™。在SBIR第一阶段，我们计划：1）合成和表征11个具有可变血清蛋白的化合物 PN-8518单个位置上的结合基团，2）在PD模型中选择最佳的两种化合物，3）检测 在患病小鼠的PD模型中最好的两种化合物，和4）在6周疾病模型中测试最好的化合物， 最后4）进行最佳化合物的PK/PD研究以预测人体剂量。强大的科学团队 在铁超载疾病和生物药物开发领域经验丰富的顾问将带领我们 选择一种可用于非临床安全性研究的候选药物，然后进行I期临床研究， 审判

Abstract The goal of this SBIR phase I is to develop new therapeutics for treatment of various iron overload diseases that involves the use of hepcidin mimetics and to identify an Investigational New Drug (IND) candidate that is effica- cious in the disease model of thalassemia. There are two predominant diseases, hemochromatosis and β-tha- lassemia, that are characterized with iron overload. In both diseases low hepcidin levels increase intestinal iron absorption and increase release of recycled iron from the reticuloendothelial system which causes depletion of macrophage iron, relatively lower levels of serum ferritin, increase in liver iron concentration, and release into the circulation of free iron that causes target-organ damage. Without treatment, iron continues to accumulate, and a considerable proportion of patients eventually reach toxic iron-overload levels. Patients are treated by phlebotomy, blood transfusions and/or iron chelators depending on the disease. Chelation therapy is associated with considerable toxicity and currently existing chelators used for treating iron overload, lack significant patient compliance or are associated with toxicity, renal impairment, hepatic impairment, and gastrointestinal hemor- rhage. Thus, there is significant need for new treatments that are safer and better tolerated. Because of hepcidins complicated 4-disulfide structure, hepcidin mimetics have been proposed as a potential therapeutic. To over- come the physicochemical limitations of hepcidin, more potent, stable, soluble and efficacious alternate scaffolds than hepcidin were engineered by using a purposefully built structure-based drug environment (Vectrix™). A lead compound (PN-8518) was identified after optimizing and profiling engineered scaffolds identified by Vec- trix™. In this SBIR phase I we plan to: 1) synthesize and characterize 11 compounds with variable serum protein binding groups on a single position of PN-8518, 2) select the best two compounds in a PD model and 3) test the best two compounds in a PD model in diseased mice, and 4) test the best compound in a 6-week disease model, and finally 4) undertake a PK/PD study of the best compound to predict human dose. A strong scientific team and consultants experienced in the field of iron overload diseases and biological drug development will lead us to select a drug development candidate that can be taken into nonclinical safety studies and then Phase I clinical trials.