Targeted Identification of Dual Acting Antisickling Agents for Sickle Cell Disease Therapy

用于镰状细胞病治疗的双重作用抗镰刀剂的靶向鉴定

基本信息

批准号：
10722861
负责人：
Osheiza Y Abdulmalik
金额：
$ 57.23万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-20 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10722861
关键词：
ADME Study Acute Affect Affinity African American population Aldehydes Anemia Antisickling Agents Binding Biological Biological Assay Blood Transfusion Cell Compartmentation Clinical Collaborations Data Derivation procedure Development Dose Endothelium Erythrocytes Exhibits FDA approved Formulation Functional disorder Funding Hematological Disease Hemoglobin Hemolysis Hydrophobicity Hypoxia In Vitro Individual Inflammation Inherited Investigation Kinetics Lead Metabolic Metabolism Minority Groups Modeling Modification Mus Mutation Organ Oxygen Parents Pathologic Pharmacodynamics Phase Polymers Property Research Personnel Safety Sickle Cell Sickle Cell Anemia Sickle Hemoglobin Structure-Activity Relationship Surface Testing Therapeutic Therapeutic Agents Therapeutic Intervention Toxic effect Validation Variant X-Ray Crystallography atomic interactions candidate selection cost design efficacy study experience health disparity hemoglobin polymer hydroxyurea improved in vivo insoluble fiber lead optimization normoxia novel novel therapeutics pharmacokinetics and pharmacodynamics pharmacologic polymerization prevent rational design scale up screening sickling stoichiometry validation studies vanillin

项目摘要

Our overall objective of this R61/R33 proposal is to design and study novel therapeutic agents for sickle cell disease (SCD) that inhibit and/or destabilize the initial, hypoxia-induced hemoglobin (Hb) polymerization, thereby reducing the subsequent secondary pathophysiology, with minimal liability for toxicity. When deoxygenated, sickle Hb polymerizes into long, rigid, and insoluble fibers, causing red blood cells (RBCs) to sickle. The proposal leverages the complementary expertise, commitment, and experience of the investigative team; and a compelling body of preliminary data to test the hypothesis that novel synthetic molecules that directly destabilize polymer formation, in addition to increasing Hb affinity for O2, will provide a superior therapeutic option for SCD. The specific aims are: 1: Design, synthesize and conduct in-vitro functional and biological assessment of novel vanillin derivatives. We have previously established novel antisickling derivatives that exhibit significant pharmacologic improvement over their parent compounds. This aim further utilizes an intricate and informed strategy to derivatize lead compounds to increase direct polymer destabilization, as well as decrease stoichiometry of compound binding to Hb. We will subject the compounds to a battery of screening assays to evaluate in-vitro functional and biological properties, to include Hb modification, inhibition of cell sickling, effect on Hb affinity for O2, and X-ray crystallography to elucidate their atomic interactions with Hb. Aim 1 studies will identify superior candidates and inform further structural modifications to enhance potency for subsequent Aim 2 studies of the R61 phase. 2: Establish Hb binding kinetics, in-vitro metabolism and ADME, and preliminary in-vivo pharmacodynamics properties of select compounds. In this concluding Aim of the R61 phase, we will conduct further validation studies on select candidates from Aim 1. Specifically, we will characterize their efficiency of partitioning into the RBC compartment and Hb binding kinetics, in-vitro metabolic and ADME/safety profiles, and preliminary in-vivo pharmacodynamic profiles. Results from the planned studies will firmly and conclusively identify and validate superior lead molecule(s) for further development in Aim 3 (R33 Phase). 3: Conduct in-vivo functional and biological studies to establish promising lead compounds for development. Aim 3 (R33) will focus on in-vivo PK/PD efficacy studies in wild-type and SCD mice. We will conduct scale-up synthesis of optimized lead molecules, optimize formulation, and formally conduct detailed in- vivo PK/PD and efficacy studies that include in-vivo modification of Hb to the non-sickling, high affinity variant; reduction in circulating sickled cells under normoxia and hypoxia; amelioration of hemolysis, inflammation, endothelial damage; and overall reversal of the SCD pathophysiology observed in this model. The novel compounds are expected to exhibit enhanced efficacy at reduced doses. We will collaborate with accelerator partners from our current list of potential candidates. We will obtain required cost-matching funds to defray the costs required to execute this phase and advance the lead(s) into the development phase.

我们 R61/R33 提案的总体目标是设计和研究镰状细胞病的新型治疗剂疾病（SCD）抑制和/或破坏最初的缺氧诱导的血红蛋白（Hb）聚合，从而减少随后的继发病理生理学，并且毒性的可能性最小。当脱氧时，镰状血红蛋白聚合成又长又硬的不溶性纤维，导致红细胞 (RBC) 形成镰状。提案利用调查团队的互补专业知识、承诺和经验；和一个令人信服的初步数据来检验以下假设：新型合成分子会直接破坏稳定性聚合物的形成，除了增加 Hb 对 O2 的亲和力之外，还将为 SCD 提供更好的治疗选择。具体目标是： 1：设计、合成并进行体外功能和生物学评估新型香草醛衍生物。我们之前已经建立了新型抗镰化衍生物，其表现出显着的对其母体化合物的药理学改进。这一目标进一步利用了复杂且知情的衍生化先导化合物以增加直接聚合物不稳定的策略，以及减少化合物与 Hb 结合的化学计量。我们将对这些化合物进行一系列筛选分析，以评估体外功能和生物学特性，包括 Hb 修饰、细胞镰状化抑制、效果 Hb 对 O2 的亲和力，以及 X 射线晶体学，以阐明它们与 Hb 的原子相互作用。目标 1 研究将确定优秀候选者并告知进一步的结构修改，以增强后续目标的效力 2 R61 相的研究。 2：建立 Hb 结合动力学、体外代谢和 ADME，以及选定化合物的初步体内药效学特性。 R61 的最终目标阶段，我们将对目标 1 中选定的候选者进行进一步的验证研究。具体来说，我们将表征它们分配到红细胞区室的效率和血红蛋白结合动力学、体外代谢 ADME/安全性概况，以及初步的体内药效学概况。计划研究的结果将坚定而最终地识别和验证卓越的先导分子，以进一步开发目标 3 (R33 阶段）。 3：进行体内功能和生物学研究，以确定有前途的先导化合物发展。目标 3 (R33) 将重点关注野生型和 SCD 小鼠的体内 PK/PD 功效研究。我们将对优化的先导分子进行放大合成，优化处方，正式进行详细in- 体内 PK/PD 和功效研究，包括将 Hb 体内修饰为非镰状、高亲和力变体；常氧和缺氧条件下循环镰状细胞减少；改善溶血、炎症、内皮损伤；以及在此模型中观察到的 SCD 病理生理学的整体逆转。小说预期化合物在减少的剂量下表现出增强的功效。我们将与加速器合作我们当前潜在候选人名单中的合作伙伴。我们将获得所需的成本匹配资金来支付执行此阶段并将潜在客户推进开发阶段所需的成本。