Hemoglobin Modifiers for Sickle Cell Disease Therapy

用于镰状细胞病治疗的血红蛋白调节剂

• 批准号: 9445715
• 负责人: Martin K Safo
• 金额: $ 2.55万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-11 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9445715
• 关键词: Acute; Adverse effects; Adverse event; Affect; Affinity; African American; Aldehydes; Antisickling Agents; Ants; Binding; Biological; Biological Assay; Biological Availability; Biological Markers; Biological Models; Blood Transfusion; Blood flow; Cell Adhesion; Cells; Cellular Morphology; Cytosol; Data; Dehydration; Disease; Disease Pathway; Disease Progression; Dose; Endothelium; Erythrocytes; Event; Exhibits; Functional disorder; Generations; Goals; Hematological Disease; Hemoglobin; Hemoglobin concentration result; Hemolysis; Hepatic; Human; Hydration status; Impairment; In Vitro; Inflammation; Inherited; Kinetics; Lead; Mediating; Metabolism; Methodology; Methods; Minority; Modeling; Modification; Monitor; Mus; Oral; Oxidative Stress; Oxygen; Pain; Parents; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Polymers; Population; Process; Prodrugs; Property; Rattus; Regimen; Research Personnel; Resources; Series; Serum Albumin; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Solubility; Structure; Surface; Survival Rate; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Tissues; Toxicology; Transgenic Mice; Variant; X-Ray Crystallography; adduct; aldehyde dehydrogenases; atomic interactions; base; cytotoxicity; design; drug candidate; experience; health care disparity; health disparity; hydroxyurea; improved; in vivo; insight; insoluble fiber; mouse model; next generation; novel; novel therapeutics; polymerization; preclinical efficacy; premature; prevent; public health relevance; research clinical testing; sickling; vanillin

DESCRIPTION (provided by applicant): Our goal is to design and establish novel therapeutic agents for sickle cell disease (SCD), namely drugs that inhibit the initial sickle hemoglobin (HbS) polymerization and the subsequent pathophysiology. When deoxygenated, HbS polymerizes into long, rigid, and insoluble fibers causing red blood cells (RBCs) to sickle, a process worsened by the unusual low affinity of HbS for oxygen, resulting in premature release of oxygen. Based on several evidence--our preliminary data, studies by others, and the results of a recently completed phase I/II clinical testing of our lead compound, 5-HMF (an allosteric effector of Hb, AEH)-we hypothesize that AEHs, not only prevent HbS polymerization, but also mitigates several secondary sickling related pathological events that include inflammation, oxidative stress/damage, RBC hemolysis, and pain. We also have preliminary evidence that our next generation AEHs (INN- and TD-series) exhibit enhanced potency and improved in-vitro duration of action. These AEHs act via a novel mechanism of action, i.e., destabilize HbS polymer contacts, in addition to increasing Hb affinity for oxygen; providing positive synergistic effects. We propose to test our hypothesis by further investigating candidate drugs from the INN- and TD-series, as well as derivatives of 5-HMF and INN-312 for their pharmacologic properties, focusing on the secondary SCD pathways, as well as the underlying HbS polymerization problem using our model systems. The specific aims are: 1. Design and synthesis of novel allosteric effectors of hemoglobin (AEHs). We will modify our parent compounds and synthesize derivatives with enhanced efficacy and prolonged half-lives. We will also synthesize prod rugs to protect the active aldehyde functional moiety from aldehyde dehydrogenase (ALDH)- mediated metabolism as necessary. 2. Investigate in-vitro functional, ant sickling, and cytotoxicity activities of novel AEHs. We will investigate the AEHs for their in-vitro ant sickling/functional activities (RBC sickling tests, P50 analyses, HbS solubility, and Hb adduct formation), and carefully monitor for adverse effects. 3. Determine in-vivo/in-vitro PK/PD properties, binding and metabolism and evaluate preclinical efficacy of AEHs in SCD Berkeley mice. We will show that serum albumin binding and/or metabolism by ALDH in RBC or hepatic cytosol are not likely to adversely affect in-vivo pharmacologic activity. We will demonstrate using a Berkeley mouse model of SCD transgenic mice that AEHs show potent pharmacologic effects, increase short- and long-term survival rates of mice. We will also study their potential beneficial effects, e.g. amelioration of hemolysis, inflammation, endothelial damage, and overall reversal of the SCD pathophysiology observed in this model. 4. Determine the atomic interactions between AEHs and Hb. X-ray crystallography will be used to validate our hypothesis that AEH potency is directly dependent upon their abilities to bind Hb with their pyridyl substituents toward the surface of the Hb molecule. The structures would provide valuable insight to help guide rational modifications for better pharmacologic properties.

描述（由申请人提供）：我们的目标是设计和建立新型的镰状细胞疾病治疗剂（SCD），即抑制初始镰状血红蛋白（HBS）的药物 聚合和随后的病理生理学。当脱氧时，HBS聚合成长，刚性和不溶性纤维，导致红细胞（RBC）对镰刀，这一过程因HBS对氧的异常低亲和力而恶化，从而导致氧气过早释放。基于几个证据 - 我们的初步数据，其他研究的研究以及最近完成的铅化合物I/II期临床测试的结果，5-HMF，5-HMF（HB的变构效应子，AEH） - 我们假设AEHS，不仅可以防止HBS聚合，还可以防止多个次要的相关的病理性痛苦，包括高潮和氧气均包括氧化均匀的氧气和氧气，并包括氧化均匀的氧化；我们还有初步证据表明，我们的下一代AEHS（Inn和TD系列）表现出增强的效力，并改善了体外行动持续时间。这些AEH通过一种新型的作用机理，即，除了增加HB对氧气的亲和力外，还会破坏HBS聚合物接触的稳定性；提供积极的协同作用。 我们建议通过进一步研究来自Inn和TD系列的候选药物，以及5-HMF和Inn-312的衍生物的药理特性，以使用我们的模型系统来关注二级SCD途径以及基本的HBS聚合问题。具体目的是：1。血红蛋白（AEHS）的新型变构效应子的设计和合成。我们将通过增强的功效和长时间的半衰期来修改母体化合物并合成衍生物。我们还将合成产品地毯，以保护活性醛功能部分免受醛脱氢酶（ALDH） - 必要时介导的代谢。 2。研究新型AEHS的体外功能，抗屁股和细胞毒性活性。我们将研究AEHS的体外抗疾病/功能活动（RBC疾病测试，P50分析，HBS溶解度和HB加合物形成），并仔细监视不良影响。 3。确定体内/维特罗PK/PD特性，结合和代谢，并评估AEHS在SCD Berkeley小鼠中的临床前疗效。我们将证明ALDH在RBC或肝细胞质中的血清白蛋白结合和/或代谢不太可能对体内药理学活性产生不利影响。我们将使用SCD转基因小鼠的伯克利小鼠模型证明AEHS表现出有效的药理作用，增加小鼠的短期和长期存活率。我们还将研究它们的潜在有益效果，例如在此模型中观察到的SCD病理生理学的溶血，炎症，内皮损伤和总体逆转的改善。 4。确定AEHS和HB之间的原子相互作用。 X射线晶体学将用于验证我们的假设，即AEH效力直接取决于它们与HB取代基与HB分子表面结合Hb的能力。这些结构将提供有价值的见解，以帮助指导理性修改以获得更好的药理特性。