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：
10375399
负责人：
Osheiza Y Abdulmalik
金额：
$ 55.97万
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 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10375399
关键词：
ADME Study Acute Affect Affinity African American population Aldehydes Anemia Antisickling Agents Binding Biological Biological Assay Blood Transfusion Cell Compartmentation Clinical Data Deoxygenated Sickle Hemoglobin 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 Pharmacology 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 cost deoxyhemoglobin design efficacy study experience health disparity hemoglobin polymer hydroxyurea in vivo insoluble fiber lead optimization normoxia novel novel therapeutics pharmacokinetics and pharmacodynamics 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.

我们的R61/R33建议的总体目标是设计和研究镰状细胞的新型治疗剂疾病（SCD）抑制和/或破坏初始，缺氧诱导的血红蛋白（Hb）聚合的稳定性，从而减少随后的继发性病理生理学，对毒性的责任最小。当脱氧时，镰刀HB聚合成长，刚性和不溶性纤维，导致红细胞（RBC）成为镰刀。提案利用调查团队的补充专业知识，承诺和经验；和引人入胜的初步数据体系来检验以下假设，即新型的合成分子直接稳定除了增加HB对O2的亲和力外，聚合物的形成还将为SCD提供出色的治疗选择。具体目的是：1：设计，合成和进行体外功能和生物学评估新颖的香草素衍生物。我们以前已经建立了新颖的反质衍生物，表现出重要的对父母化合物的药理改进。这个目标进一步利用了复杂的知情衍生铅化合物以增加直接聚合物不稳定并减少的策略化合物结合与Hb的化学计量法。我们将对化合物进行一系列筛选测定评估体外功能和生物学特性，包括HB修饰，抑制细胞病，效果在HB对O2的亲和力和X射线晶体学上，以阐明其与HB的原子相互作用。 AIM 1研究将确定卓越的候选人并为进一步的结构修改提供信息，以提高效力 2 R61期的研究。 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。在R61的这个总结中阶段，我们将对AIM 1的某些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RBC室和HB结合动力学的效率，即体外代谢以及ADME/安全概况，以及初步的体内药效学概况。计划研究的结果将牢固，最终识别和验证上铅分子以进一步发展AIM 3（R33 阶段）。 3：进行体内功能和生物学研究以建立有希望的铅化合物发展。 AIM 3（R33）将重点关注野生型和SCD小鼠的体内PK/PD疗效研究。我们将进行优化的铅分子的规模合成，优化配方，并正式进行详细的详细说明 Vivo PK/PD和功效研究，包括对HB进行体内修改为非助攻，高亲和力变体；在常氧和缺氧下减少循环镰状细胞；改善溶血，炎症，内皮损害；以及在该模型中观察到的SCD病理生理学的总体逆转。小说预计化合物在降低剂量时表现出增强的功效。我们将与加速器合作我们当前潜在候选人名单的合作伙伴。我们将获得所需的成本匹配资金，以支付执行此阶段并将潜在客户推向发展阶段所需的成本。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Quantitative assessment of the in-vitro binding kinetics of antisickling aromatic aldehydes with hemoglobin A: A universal HPLC-UV/Vis method to quantitate Schiff-base adduct formation.

抗镰化芳香醛与血红蛋白 A 的体外结合动力学的定量评估：定量席夫碱加合物形成的通用 HPLC-UV/Vis 方法。

DOI：
10.1016/j.jpba.2022.115152
发表时间：
2023
期刊：
Journal of pharmaceutical and biomedical analysis
影响因子：
3.4
作者：
Xu,Xiaomeng;Ghatge,MohiniS;Huang,Boshi;Alghamdi,Ahmed;Wang,Huiqun;Pierce,BDaniel;Abdulmalik,Osheiza;Zhang,Yan;Safo,MartinK;Venitz,Jürgen
通讯作者：
Venitz,Jürgen

Design, Synthesis, and Antisickling Investigation of a Nitric Oxide-Releasing Prodrug of 5HMF for the Treatment of Sickle Cell Disease.

DOI：
10.3390/biom12050696
发表时间：
2022-05-12
期刊：
BIOMOLECULES
影响因子：
5.5
作者：
Alhashimi, Rana T.;Ghatge, Mohini S.;Donkor, Akua K.;Deshpande, Tanvi M.;Anabaraonye, Nancy;Alramadhani, Dina;Danso-Danquah, Richmond;Huang, Boshi;Zhang, Yan;Musayev, Faik N.;Abdulmalik, Osheiza;Safo, Martin K.
通讯作者：
Safo, Martin K.

Metabolic Reprogramming in Sickle Cell Diseases: Pathophysiology and Drug Discovery Opportunities.

DOI：
10.3390/ijms23137448
发表时间：
2022-07-04
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
通讯作者：

Elucidating the Interaction between Pyridoxine 5'-Phosphate Oxidase and Dopa Decarboxylase: Activation of B6-Dependent Enzyme.

DOI：
10.3390/ijms24010642
发表时间：
2022-12-30
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Al Mughram MH;Ghatge MS;Kellogg GE;Safo MK
通讯作者：
Safo MK

Design, Synthesis, and Investigation of Novel Nitric Oxide (NO)-Releasing Aromatic Aldehydes as Drug Candidates for the Treatment of Sickle Cell Disease.

DOI：
10.3390/molecules27206835
发表时间：
2022-10-12
期刊：
MOLECULES
影响因子：
4.6
作者：
Huang, Boshi;Ghatge, Mohini S.;Donkor, Akua K.;Musayev, Faik N.;Deshpande, Tanvi M.;Al-Awadh, Mohammed;Alhashimi, Rana T.;Zhu, Hongmei;Omar, Abdelsattar M.;Telen, Marilyn J.;Zhang, Yan;McMahon, Tim J.;Abdulmalik, Osheiza;Safo, Martin K.
通讯作者：
Safo, Martin K.