The development of novel peptidic and peptidomimetic therapies for the treatment

新型肽和拟肽疗法的开发

• 批准号: 8289878
• 负责人: Brian Buerk Brennan
• 金额: $ 28.52万
• 依托单位: ILLINOIS WESLEYAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8289878
• 关键词: Affect; Amino Acids; Arts; Attention; Bacteriophages; Binding; Binding Sites; Biological Assay; Blood capillaries; Cells; Characteristics; Code; Development; Development Plans; Disease; Drug Industry; Erythrocytes; Fiber; Fluorescence; Fluorescence Spectroscopy; Funding Mechanisms; Generations; Genes; Genetic; Glutamic Acid; Hematological Disease; Hemoglobin; Hydrophobic Surfaces; Hypoxia; Institution; Lead; Libraries; Ligands; Measures; Membrane Proteins; Methods; Molecular; Organ; Oxygen; Oxyhemoglobin; Pain; Peptide Library; Peptides; Peptoids; Permeability; Phage Display; Phase; Point Mutation; Polymers; Property; Proteins; Relative (related person); Research; Screening procedure; Series; Shapes; Sickle Cell; Sickle Cell Anemia; Site; Solid; Surface; Techniques; Testing; Therapeutic; Therapeutic Effect; Tissues; Training; United States; Valine; Variant; Work; biological systems; capillary; crosslink; design; effective therapy; improved; intermolecular interaction; malformation; novel; novel strategies; novel therapeutics; peptidomimetics; polymerization; prevent; research study; sickling; therapeutic development; three dimensional structure; tool; treatment strategy; undergraduate student

DESCRIPTION (provided by applicant): Sickle-cell disease (SCD) is a genetic blood disorder that is characterized by the presence of sickle-shaped red blood cells. These "sickled" cells clog small capillaries, leading to severe pain and organ damage [2]. The disease is the result of a single point mutation in the gene coding for the ¿-chain of hemoglobin (Hb), leading to the incorporation of a valine surface residue in place of glutamic acid [1]. Under low oxygen conditions, a binding surface for the valine residue is revealed at the EF-helix interface also on the ¿-chain. An intermolecular interaction occurs leading to polymerization of deoxygenated sickle-cell hemoglobin (HbS) and the characteristic sickling of the red blood cells (RBCs) [1]. Despite the fact that the molecular mechanism of SCD is well understood, no effective treatment exists [4]. Therefore, the discovery of molecules capable of preventing HbS polymerization would be highly desirable. Peptides and peptidomimetics have proven to be powerful tools for the manipulation of biological systems in a number of different contexts. Most relevant is their ability to bind to protein surfaces and disrupt key protein interactions [18-20, 30]. Several techniques are currently available for the discovery of peptidic and peptidomimetic compounds capable of serving as protein ligands [14,15]. The research plan for the development of novel therapeutics for sickle cell disease is three-fold. (1) Several one-bead-one- compound solid-phase libraries will be screened against HbS. The libraries are designed to bind to HbS in a manner capable of leading to the disruption of the key contact sites that lead to HbS polymer formation. It is hypothesized that these molecules will disrupt HbS polymerization. (2) Phage display libraries will be screened against oxygenated HbS, leading to the discovery of molecules that stabilize oxyhemoglobin, thereby preventing fiber formation. (3) Characterization of the ligands by fluorescence spectroscopy and photo-crosslinking will provide valuable information on the important contacts and allow for the synthesis of more potent second-generation ligands. This work represents a novel approach for development of therapeutics for this disease and provides an ideal training ground for undergraduate students, both of which fit the objectives of the R15 funding mechanism. PUBLIC HEALTH RELEVANCE: Sickle cell disease affects nearly 100,000 people in the United States, yet an effective treatment does not yet exist. Because of its relative low occurrence, it has not garnered significant attention from the pharmaceutical industry. The research proposed is the first step in defining the feasibility of a new strategy for treating this disorder through the use of modern screening and selection techniques.

描述（由申请人提供）：镰状细胞病（SCD）是一种以镰状红细胞存在为特征的遗传性血液疾病。这些“镰状”细胞堵塞毛细血管，导致严重的疼痛和器官损伤。这种疾病是血红蛋白（Hb）编码基因的单点突变的结果，导致缬氨酸表面残基取代谷氨酸[1]。在低氧条件下，缬氨酸残基的结合面在ef -螺旋界面上也在¿-链上出现。分子间相互作用导致脱氧镰状细胞血红蛋白（HbS）聚合和红细胞（rbc）[1]的特征性镰状反应。尽管SCD的分子机制已经很清楚，但目前还没有有效的治疗方法。因此，发现能够阻止HbS聚合的分子将是非常可取的。在许多不同的情况下，多肽和多肽拟物已被证明是操纵生物系统的有力工具。最相关的是它们与蛋白质表面结合并破坏关键蛋白质相互作用的能力[18- 20,30]。目前有几种技术可用于发现能够作为蛋白质配体的肽类和拟肽类化合物[14,15]。开发镰状细胞病新疗法的研究计划有三个方面。(1)对几种单头一化合物固相文库进行HbS筛选。这些文库被设计成以一种能够破坏导致HbS聚合物形成的关键接触位点的方式与HbS结合。据推测，这些分子会破坏HbS聚合。(2)噬菌体展示文库将针对氧合血红蛋白进行筛选，从而发现稳定氧合血红蛋白的分子，从而防止纤维形成。(3)通过荧光光谱和光交联对配体的表征将提供有关重要接触的有价值的信息，并允许合成更有效的第二代配体。这项工作代表了一种开发这种疾病治疗方法的新方法，并为本科生提供了理想的培训场所，这两者都符合R15资助机制的目标。