The development of novel peptidic and peptidomimetic therapies for the treatment

描述(申请人提供)：镰状细胞病(SCD)是一种遗传性血液疾病，以镰刀状红细胞的存在为特征。这些“镰状”细胞堵塞小毛细血管，导致剧烈疼痛和器官损伤[2]。这种疾病是由编码血红蛋白(Hb)链的基因的单点突变导致的，导致在谷氨酸的位置加入了Valine表面残基[1]。在低氧条件下，Valine残基的结合表面在EF-螺旋界面上也在？-链上。分子间的相互作用导致脱氧镰状细胞血红蛋白(HBS)的聚合和红细胞(RBC)的特征镰刀状[1]。尽管SCD的分子机制已被熟知，但目前尚无有效的治疗方法[4]。因此，能够阻止HBS聚合的分子的发现将是非常可取的。多肽和多肽仿生学已被证明是在许多不同环境中操纵生物系统的强大工具。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多肽和模拟多肽化合物[14，15]。开发治疗镰状细胞病的新疗法的研究计划有三个方面。(1)对几个一珠一化合物固相库进行HBS筛选。这些文库被设计成以一种能够导致破坏导致HBS聚合物形成的关键接触位点的方式与HBS结合。据推测，这些分子将破坏HBS聚合。(2)噬菌体展示文库将针对含氧的HBS进行筛选，从而发现稳定含氧血红蛋白的分子，从而防止纤维形成。(3)用荧光光谱和光交联法表征配体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的治疗方法的新方法，并为本科生提供了一个理想的培训场所，两者都符合R15资助机制的目标。 与公共卫生相关：在美国，镰状细胞病影响着近10万人，但尚不存在有效的治疗方法。由于其相对较低的发生率，它并没有引起制药行业的显著关注。提出的研究是确定治疗这种疾病的新策略的可行性的第一步。 通过使用现代筛查和选择技术来消除疾病。

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.