Ferristatin: A New Small Molecule Inhibitor of Iron Transport

Ferristatin：一种新的铁转运小分子抑制剂

• 批准号: 7831012
• 负责人: Marianne Wessling-Resnick
• 金额: $ 47.98万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7831012
• 关键词: Address; Alleles; Anemia; Area; Binding; Biochemical Process; Biochemistry; Caucasians; Caucasoid Race; Country; Development; Diagnostic; Dietary Iron; Disease; Drug Kinetics; Emerging Technologies; Endosomes; Enterocytes; Erythroid; Erythroid Cells; Fluorescence; Foundations; Genes; Genetic Models; Goals; Health; Hemochromatosis; Hepatic; Hereditary Disease; Hereditary hemochromatosis; Homeostasis; Intestines; Iron; Iron Overload; Iron-Binding Proteins; Knockout Mice; Knowledge; Mediating; Modeling; National Institute of Diabetes and Digestive and Kidney Diseases; Nutritional; Pathogenesis; Pathway interactions; Population; Predisposition; Rattus; Research; SLC11A2 gene; Screening procedure; Serum; Therapeutic; Transferrin; Translating; Translational Research; Transport Process; absorption; apical membrane; base; chemical genetics; genetic variant; high throughput screening; in vivo; inhibitor/antagonist; novel therapeutics; public health relevance; receptor mediated endocytosis; small molecule; tool; transport inhibitor; uptake

DESCRIPTION (provided by applicant): This application addresses the broad Challenge Area 15, Translational Sciences, and specific challenge topic 15-DK-103: Translate discovery of new molecules and pathways in pathogenesis of NIDDK diseases into potential therapies, diagnostics, or research tools. The biochemistry of iron transport is not thoroughly understood. Although iron deficiency is the most prevalent nutritional problem in the U.S., 1 in 20 Caucasians carry genetic variants of HFE alleles that promote susceptibility to iron overload. Thus, there is a need to develop new therapeutic strategies for diseases of both iron deficiency and overload. Through high-throughput fluorescence-based screening, our lab recently discovered that ferristatin (NSC306711) inhibits both of the major iron transport processes that maintain homeostasis: transferrin- mediated iron uptake and non-transferrin-bound iron uptake by Divalent Metal Transporter 1 (DMT1). Chlorazol black (NSC8679) is structurally similar and has comparable effects on transport. This project will further investigate the impact of these two small molecules and related compounds in vivo, on a) pharmacokinetics of intestinal iron uptake to the vasculature; b) iron uptake into erythroid cells and hepatic non-transferrin bound iron uptake; and c) iron homeostasis and reversal of overload. These efforts will further our goals to elucidate the biochemical processes regulating iron homeostasis, and to provide a foundation for the development of targeted small-molecule therapies for states of anemia and hemochromatosis. PUBLIC HEALTH RELEVANCE: Iron deficiency remains the most prevalent nutritional problem in our country, yet recent identification of the gene responsible for hereditary hemochromatosis indicates that 1 in 20 Caucasians carry the defective allele and thus 1 in 400 may be susceptible to iron overload. Increased knowledge about the transport factors and how they protect against iron deficiency and overload is essential to more broadly address these significant health problems.

描述（由申请人提供）：本申请涉及广泛的挑战领域15，转化科学和特定的挑战主题15-DK-103：将NIDDK疾病发病机制中的新分子和途径的发现转化为潜在的治疗，诊断或研究工具。铁转运的生物化学尚未完全了解。虽然缺铁是美国最普遍的营养问题，1/20的高加索人携带HFE等位基因的遗传变异，促进对铁过载的易感性。因此，需要开发用于铁缺乏和铁超负荷的疾病的新的治疗策略。通过高通量荧光筛选，我们的实验室最近发现，铁蛋白抑制素（NSC 306711）抑制维持体内平衡的两个主要铁转运过程：转铁蛋白介导的铁摄取和二价金属转运蛋白1（DMT 1）的非转铁蛋白结合铁摄取。氯唑黑（NSC 8679）结构相似，对转运的影响相当。本项目将进一步研究这两种小分子和相关化合物在体内对以下方面的影响：a）肠道铁摄取至脉管系统的药代动力学; B）红系细胞铁摄取和肝脏非转铁蛋白结合铁摄取;以及c）铁稳态和超负荷逆转。这些努力将进一步阐明调节铁稳态的生化过程，并为开发针对贫血和血色病状态的靶向小分子疗法提供基础。 公共卫生关系：铁缺乏仍然是我国最普遍的营养问题，但最近对遗传性血色病基因的鉴定表明，每20名高加索人中就有1人携带缺陷等位基因，因此每400人中就有1人可能易患铁过载。增加对运输因素的了解以及它们如何防止铁缺乏和过载对于更广泛地解决这些重大健康问题至关重要。