A PSGL-1 Glycopeptide Mimetic for Treatment of Venous Thromboembolism

用于治疗静脉血栓栓塞的 PSGL-1 糖肽模拟物

• 批准号: 9118358
• 负责人: Elliot Chaikof
• 金额: $ 41.78万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9118358
• 关键词: Acute; Affinity; Anticoagulation; Binding; Carbohydrates; Chemicals; Chronic; Computer Simulation; Deep Vein Thrombosis; Development; Dose; Drug Delivery Systems; Drug Design; Drug Kinetics; E-Selectin; Effectiveness; Epitopes; Event; Fibrosis; Generations; Glycopeptides; Health; Hemorrhage; Human; In Vitro; Inflammatory Response; Investigation; L-Selectin; Lead; Leukocytes; Ligands; Malignant Neoplasms; Metabolic; Modeling; Modification; Monosaccharides; Mus; P-Selectin; P-selectin ligand protein; Patients; Peptides; Phase; Postphlebitic Syndrome; Prevention; Prevention strategy; Primates; Property; Pulmonary Embolism; Pulmonary Hypertension; Rattus; Recurrence; Regimen; Resolution; Risk; Risk Factors; Scheme; Selectins; Series; Specificity; Surface; Therapeutic Agents; Thromboembolism; Thrombosis; Thrombus; Tissues; Variant; Veins; Venous; Venous Thrombosis; analog; chemical synthesis; clinically relevant; computer studies; design; ethylene glycol; flexibility; improved; in vivo; inhibitor/antagonist; mimetics; molecular dynamics; mouse model; nanomolar; novel; patient population; prevent; programs; scaffold; screening; structural biology; thrombolysis; tumor

 DESCRIPTION (provided by applicant): We currently lack therapies that reduce the risk of deep vein thrombosis without an attendant risk of bleeding or that significantly alter the development of postthrombotic syndrome. In this proposal, we postulate that P-selectin glycoprotein ligand-1 (PSGL-1), which is a ligand for P-, L-, and E-selectin provides a starting for the design of a new series of glycomimetic analogs that will suppress venous thrombosis, promote thrombus resolution, and limit late tissue remodeling events. In this regard, we have determined that GSnP-6, as a stable, high-affinity PSGL-1 mimetic, affords a unique structural scaffold for the design of a broad range of highly potent selectin-specific antagonists. Specifically, we intend to: (1) Define the potency of GSnP-6 in murine models of venous thrombosis. In the first phase of our investigations, we will define the pharmacokinetic profile of GSnP-6, as well as poly (ethylene glycol) (PEG) conjugates of GSnP-6. The dosing regimen affording the best drug delivery profile will be selected for subsequent in vivo studies. In the second phase of these investigations, the efficacy of GSnP-6 will be defined using occlusive and non-occlusive murine models of acute and chronic venous thrombosis. These studies will allow us to define the capacity of GSnP-6 to prevent the initiation and propagation of venous thrombosis, promote thrombus resolution, and limit late tissue remodeling events. (2) Design new structurally simpler PSGL-1 glycomimetics that display high selectin binding affinity. Preliminary molecular dynamics simulations have indicated that not all of the monosaccharides in the native PSGL-1 ligand or GSnP-6 contribute directly to binding affinity. This observation provides an opportunity to greatly simplify chemical synthesis by replacing non-critical residues with simpler structural analogs. MD simulations will be performed for free and bound forms of a series of proposed simplified structural variants of GSnP-6 to P-selectin. Structural variants that display the largest negative total interaction energy with P- selectin, which is predictive of a hih affinity selectin inhibitor, will be selected for synthesis, as well as characterization in vitro ad in vivo. The analog with the greatest potency will be selected for further investigation in occlusive and non-occlusive murine models of venous thrombosis. (3) Determine the effectiveness of GSnP-6 and related analogs in murine models of cancer associated venous thrombosis. Malignancy is a major risk factor for venous thromboembolism and despite optimal anticoagulation the risk of recurrent thrombosis and bleeding complications is substantially increased in this patient population. In the first phase of these investigations, the efficacy of GSnP-6 in the prevention and treatment of venous thrombosis will be assessed in tumor bearing mice. In the second phase, promising structurally simplified selectin antagonists that have been identified in Aim 2 will be assessed for their capacity to inhibit venous thrombosis and limit the development of postthrombotic syndrome in tumor bearing mice.

 描述（由申请人提供）：我们目前缺乏降低深静脉血栓形成风险而不伴随出血风险或显著改变血栓后综合征发展的治疗方法。在这个建议中，我们假设P-选择素糖蛋白配体-1（PSGL-1），这是一个P-，L-和E-选择素的配体，提供了一个开始设计一系列新的糖类似物，将抑制静脉血栓形成，促进血栓的解决，并限制后期组织重塑事件。在这方面，我们已经确定，GSnP-6，作为一个稳定的，高亲和力的PSGL-1模拟物，提供了一个独特的结构支架的设计范围广泛的高度有效的选择素特异性拮抗剂。具体而言，我们打算：（1）确定GSnP-6在静脉血栓形成小鼠模型中的效力。在我们研究的第一阶段，我们将确定 GSnP-6以及GSnP-6的聚（乙二醇）（PEG）缀合物。将选择提供最佳药物递送特征的给药方案用于随后的体内研究。在这些研究的第二阶段，将使用急性和慢性静脉血栓形成的闭塞性和非闭塞性鼠模型来定义GSnP-6的功效。这些研究将使我们能够确定GSnP-6预防静脉血栓形成的起始和传播、促进血栓消退和限制晚期组织重塑事件的能力。(2)设计新的结构更简单的PSGL-1糖模拟物，显示高选择素结合亲和力。初步的分子动力学模拟表明，并非所有的天然PSGL-1配体或GSnP-6中的单糖直接有助于结合亲和力。这一观察结果提供了一个机会，大大简化化学合成，取代非关键的残基与更简单的结构类似物。将对GSnP-6至P-选择素的一系列拟议简化结构变体的自由和结合形式进行MD模拟。结构变体， 显示与P-选择素的最大负总相互作用能，这预示着高亲和力选择素抑制剂，将被选择用于合成，以及体外和体内表征。将选择具有最大效力的类似物用于在静脉血栓形成的闭塞性和非闭塞性小鼠模型中进行进一步研究。(3)确定GSnP-6和相关类似物在癌症相关静脉血栓形成的鼠模型中的有效性。血栓形成是静脉血栓栓塞的主要风险因素，尽管抗凝效果最佳，但该患者人群中复发性血栓形成和出血并发症的风险显著增加。在这些研究的第一阶段，将在荷瘤小鼠中评估GSnP-6在预防和治疗静脉血栓形成中的功效。在第二阶段，将评估目标2中已鉴定的有前途的结构简化的选择素拮抗剂抑制静脉血栓形成和限制荷瘤小鼠中血栓形成后综合征发展的能力。