Synthetic glycosaminoglycan mimetics as regulators of megakaryopoiesis and thrombopoiesis

作为巨核细胞生成和血小板生成调节剂的合成糖胺聚糖模拟物

• 批准号: 10558574
• 负责人: Daniel Kwame Afosah
• 金额: $ 17.94万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10558574
• 关键词: Advanced Development; Advisory Committees; Affinity; Binding; Binding Proteins; Biological; Biological Assay; Biology; Biopolymers; Blood; Blood Circulation; Blood Platelets; Bone Marrow; Career Choice; Charge; Chemicals; Coagulation Process; Complex; Coupled; Crystallography; Cytoplasm; Data; Development; Development Plans; Dimerization; Disease; Drug Targeting; Ensure; Environment; Excision; Extracellular Matrix; Flavonoids; Foundations; Funding; Generations; Glycosaminoglycans; Hematopoietic stem cells; Heparitin Sulfate; Human; ITIM; In Vitro; Inflammation; Length; Letters; Libraries; Malignant Neoplasms; Megakaryocytes; Megakaryocytopoieses; Mentored Clinical Scientist Development Program; Mentors; Mentorship; Mission; Molecular; Mus; National Heart, Lung, and Blood Institute; Nature; Organic Synthesis; Outcome; Pattern; Pharmaceutical Preparations; Photoaffinity Labels; Plasma; Platelet Count measurement; Play; Postdoctoral Fellow; Preparation; Process; Production; Proteins; Proteomics; Public Health; Records; Regulation; Research; Research Personnel; Research Proposals; Research Training; Resources; Role; Signal Transduction; Stream; Structure; Structure-Activity Relationship; Sulfate; Surface Plasmon Resonance; Therapeutic; Therapeutic Agents; Thrombocytopenia; Thrombopoiesis; Thrombosis; United States National Institutes of Health; Validation; X-Ray Crystallography; analog; analytical ultracentrifugation; biomacromolecule; biophysical analysis; biophysical techniques; career; career development; chemical property; computer studies; experience; functional mimics; high throughput screening; in vivo; innovation; member; mimetics; molecular modeling; novel; prevent; promoter; receptor; scaffold; screening; skills; small molecule; small molecule libraries; stem; sugar; therapeutic development; three dimensional structure

PROJECT SUMMARY Title: Synthetic glycosaminoglycan mimetics as regulators of megakaryopoiesis and thrombopoiesis. Key Words: Platelets, Glycosaminoglycans, thrombopoiesis, G6b-B, NSGMs The Candidate is an NIH K12 postdoctoral scholar on an academic career path. His focus is on the roles of glycosaminoglycans (GAGs) in thrombopoiesis. He has significant research experience studying GAG–protein interactions, and a strong background in organic synthesis notably, the preparation of aromatic-scaffold-based GAG mimetics known as non-saccharide GAG mimetics (NSGMs), which are functional mimics of GAGs. Career Development Plan: This proposal is well structured and involves 2 years of mentored research training, which will ensure that the candidate develops advanced research skills critical for an independent academic career. He has assembled an advisory committee of experienced and well-funded PIs, with proven track records of mentoring young academic researchers. He also has a well-resourced environment for the proposed research. Research Plan: The number of circulating platelets is tightly balanced through continuous production and removal of platelets to prevent potentially detrimental thrombosis. Platelets are produced through sequential processes, wherein hematopoietic stem cells commit to the formation of megakaryocytes (megakaryopoiesis), which release cytoplasmic extensions into the blood stream to produce platelets (thrombopoiesis). While some mechanisms and molecular regulators of these process have been identified, much remains to be elucidated. Of these, the roles of extracellular matrix and GAGs are poorly characterized. Although GAGs are regulators of various proteins, their heterogeneous nature and the challenges associated with obtaining homogeneous forms of these complex biomacromolecules remain bottlenecks for elucidating their biological roles. Our lab has developed a diverse chemical library of NSGMs which possess an aromatic scaffold carrying multiple sulfate groups mimicking the sulfated sugar scaffold of GAGs. NSGMs bind and selectively modulate several GAG- binding proteins involved in diseases, and thus serve as excellent chemical biology probes of GAG function. We have identified G4.1, a flavonoid-based NSGM as having potent thrombopoietic potential in vitro and in vivo. Our preliminary studies show that G4.1 binds with high affinity to G6b-B, an inhibitory receptor found on megakaryocytes and platelets, involved in the regulation of platelet production. Our studies also show that G4.1 promotes G6b-B dimerization, which is required for downstream signaling. Based on this data, we hypothesize that, G4.1 promotes thrombopoiesis, in part, by its highly selective interaction with G6b-B. We will determine the nature of the interaction of G4.1 with G6b-B, probe the selectivity of G4.1 for G6b-B, and elucidate the structure- activity-relationship (SAR) of this class of compounds. This research proposal benefits from; 1) the candidate’s personal track-record, 2) robust preliminary data, 3) a highly experienced advisory committee with relevant expertise to the proposed research, and 4) a supportive and well-resourced research environment. The three aims of the proposal are : I) Determine the nature of interaction of G4.1 with G6b-B, II) Evaluate the selectivity of G4.1 recognition of G6b-B, and III) Synthesize a library of G4.1 analogs and elucidate SAR.

项目概要 标题：合成糖胺聚糖模拟物作为巨核细胞生成和血小板生成的调节剂。 关键词: 血小板, 糖胺聚糖, 血小板生成, G6b-B, NSGM 候选人是一位 NIH K12 博士后学者，其学术职业道路上的重点是以下角色。 他在 GAG 蛋白方面拥有丰富的研究经验。 相互作用，以及有机合成方面的强大背景，尤其是基于芳香族支架的制备 GAG模拟物又称为非糖类GAG模拟物（NSGMs），是GAG的功能模拟物。 发展计划：该提案结构良好，涉及 2 年指导研究培训，其中 将确保候选人发展对独立学术生涯至关重要的先进研究技能。 他组建了一个由经验丰富且资金充足的 PI 组成的咨询委员会，这些 PI 拥有良好的业绩记录 他还为拟议的研究提供了充足的资源环境。 研究计划：通过连续生产和维持循环血小板数量的紧密平衡 去除血小板以防止潜在的不健康血栓形成 血小板是通过连续产生的。 过程，导致造血干细胞致力于形成巨核细胞（巨核细胞生成）， 其将细胞质延伸物释放到血流中以产生血小板（血小板生成）。 这些过程的机制和分子调节剂已经确定，但仍有许多问题有待阐明。 尽管 GAG 是细胞外基质和 GAG 的调节剂，但其作用尚不清楚。 各种蛋白质、它们的异质性以及与获得同质形式相关的挑战 这些复杂的生物大分子仍然是阐明其生物学作用的瓶颈。 开发了 NSGM 的多样化化学库，其具有携带多种硫酸盐的芳香族支架 模仿 GAG 的硫酸化糖支架的基团结合并选择性地调节多种 GAG- 与疾病相关的结合蛋白，因此可作为 GAG 功能的优秀化学生物学探针。 我们已经鉴定出 G4.1，一种基于类黄酮的 NSGM，在体外和体内具有强大的血小板生成潜力。 初步研究表明，G4.1 以高亲和力与 G6b-B 结合，G6b-B 是一种在 我们的研究还表明，巨核细胞和血小板参与血小板生成的调节。 促进 G6b-B 二聚化，这是下游信号传导所必需的。根据这些数据，我们陷入了困境。 G4.1 部分地通过其与 G6b-B 的高度选择性相互作用来促进血小板生成。 G4.1与G6b-B相互作用的性质，探测G4.1对G6b-B的选择性，并阐明结构- 此类化合物的活性关系 (SAR) 受益于 1) 候选者的； 个人跟踪记录，2）可靠的初步数据，3）经验丰富的咨询委员会 拟议研究的专业知识，以及 4) 支持性且资源充足的研究环境。 该提案的目标是：I) 确定 G4.1 与 G6b-B 相互作用的性质，II) 评估选择性 G4.1 识别 G6b-B，以及 III) 合成 G4.1 类似物文库并阐明 SAR。

项目成果

Designing Smaller, Synthetic, Functional Mimetics of Sulfated Glycosaminoglycans as Allosteric Modulators of Coagulation Factors.

设计更小的、合成的、硫酸化糖胺聚糖的功能模拟物作为凝血因子的变构调节剂。

• 发表时间: 2023-04-13
• 影响因子: 7.3
• 作者: Abdelfadiel, Elsamani I;Gunta, Rama;Villuri, Bharath Kumar;Afosah, Daniel K;Sankaranarayanan, Nehru Viji;Desai, Umesh R
• 通讯作者: Desai, Umesh R

Investigation of the anticoagulant activity of cyclic sulfated glycosaminoglycan mimetics.

环状硫酸化糖胺聚糖模拟物的抗凝血活性的研究。

• 发表时间: 2023-07
• 影响因子: 3.1
• 作者: Chiles, Raquel;Afosah, Daniel K;Al
• 通讯作者: Al

Homogeneous, Synthetic, Non-Saccharide Glycosaminoglycan Mimetics as Potent Inhibitors of Human Cathepsin G.

均质、合成、非糖胺聚糖模拟物作为人组织蛋白酶 G 的有效抑制剂。

• 发表时间: 2023-04-27
• 影响因子: 5.5
• 作者: Afosah, Daniel K;Fayyad, Rawan M;Puliafico, Valerie R;Merrell, Spencer;Langmia, Eltice K;Diagne, Sophie R;Al;Desai, Umesh R
• 通讯作者: Desai, Umesh R