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Sulfated Poly-Amido-Saccharide (sulPAS) Biomaterials as Anticoagulants

作为抗凝剂的硫酸化聚酰胺糖 (sulPAS) 生物材料

基本信息

批准号：
10649522
负责人：
Elliot Chaikof
金额：
$ 56.25万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649522
关键词：
Address African Animals Anticoagulants Asfarviridae Biocompatible Materials Biological Biological Assay Bleeding time procedure Blood Coagulation Disorders Carbohydrates Cattle Cells Cessation of life Chemical Structure Chemicals Circular Dichroism Classical Swine Fever Clinical Coagulation Process Collaborations Complication Data Disease Disease Management Dose Double Stranded DNA Virus Drug Kinetics Elements Enoxaparin Epidemic Exhibits Experimental Designs Family Family suidae Gel Chromatography Glucose Half-Life Hemorrhage Hemostatic function Heparin Human In Vitro Intravenous Lead Left Life Low-Molecular-Weight Heparin Modernization Molecular Molecular Weight Mucous Membrane NMR Spectroscopy Operative Surgical Procedures Patients Performance Plasma Polymers Polysaccharides Population Positioning Attribute Protamine Sulfate Protease Inhibitor Prothrombin time assay Reaction Risk Rodent Model Serine Protease Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Spectrum Analysis Structure Structure-Activity Relationship Sulfate Testing Therapeutic Thrombin Time Assay Toxic effect Variant Venous Thrombosis Vertebral column Viral Hemorrhagic Fevers beta-Lactams cytotoxicity depolymerization efficacy study experimental study fondaparinux heparanase heparin-induced thrombocytopenia hydrophilicity improved in vivo infrared spectroscopy innovation interest intravenous administration mimetics monomer novel pharmacokinetics and pharmacodynamics polymerization polysulfated glycosaminoglycan prevent pyranose response side effect subcutaneous sugar supply chain

项目摘要

PROJECT SUMMARY/ABSTRACT This proposal describes a novel biomaterial and synthetic anticoagulant. Anticoagulants are a mainstay of modern surgery and of clotting disorder management such as venous thrombosis, yet performance and supply limitations exist for the most widely used agent - heparin. Specifically, heparin’s heterogeneous structure affords highly variable activity, patient-dependent dose-responses, and life-threatening side effects such as heparin induced thrombocytopenia. Additionally, African Swine Fever (a double-stranded DNA virus in the Asfarviridae family) has wiped out over one-quarter of the world’s pig population leading to global shortages, contamination issues, and the need for alternatives – i.e., anticoagulants of non-animal origin. We propose the use of disulfated poly-amido-saccharides (PASs) as heparin mimetics. PASs are new well- defined, enantiopure carbohydrate polymers that are stereochemically defined, hydrophilic, and possess pyranose rings in the backbone. PASs are efficiently synthesized by the anionic ring-opening polymerization reaction of a β-lactam sugar monomer in high-yields with batch-to-batch consistency, defined molecular weights, and low polydispersity. Sulfation of PAS yields such unique heparin mimetics. Herein, we describe the novel synthesis along with detailed in vitro and ex vivo mechanism-of-action and in vivo efficacy studies. The proposed experiments will define the molecular and structural basis for anticoagulant activity of disulfated PAS (disulPAS) and will test the hypothesis that regioselectively functionalized disulPASs will be: 1) efficacious in vivo with activity equivalent to or better than low molecular weight heparin (LMWH); and 2) neutralized by protamine sulfate unlike synthetic Fondaparinux. Further, sulPAS anticoagulant activity will depend on the number and the position of sulfate functionalization and not be associated with heparin-induced thrombocytopenia. Importantly, substantial preliminary data support the proposed studies, well-characterized materials and rigorous experimental designs are established, and essential cross-disciplinary collaborations and expertise are in place to address the hypotheses. The specific aims of this five-year proposal are as follows. Aim 1 synthesizes and characterizes new regioselectively disulfated PAS. Aim 2 evaluates the in vitro/ex vivo anticoagulant activity and determines the mechanism of action (MOA) of disulfated PASs. Aim 3 defines the pharmacokinetic and pharmacodynamic profile of lead disulPAS candidates and efficacy in rodent models of thromboprophylaxis and bleeding risk.

项目总结/摘要该提案描述了一种新型生物材料和合成抗凝剂。抗凝血剂是主要的现代手术和凝血障碍管理，如静脉血栓形成，但性能和对于最广泛使用的试剂-肝素存在供应限制。具体来说，肝素的异质性结构提供高度可变的活性、患者依赖性剂量反应和危及生命的副作用例如肝素诱导的血小板减少症。此外，非洲猪瘟（一种双链DNA病毒，在阿斯法尔病毒科）已经消灭了超过四分之一的世界猪种群，导致全球短缺、污染问题以及对替代品的需求--即，非动物来源的抗凝剂。我们建议使用二硫酸化聚酰胺-聚（PAS）作为肝素模拟物。PAS是新的好- 确定的、对映体纯的碳水化合物聚合物，其是立体化学确定的、亲水的，并且具有骨架中的吡喃糖环。阴离子开环聚合法是合成PAS的有效方法 β-内酰胺糖单体的高产率反应，具有批间一致性，确定的分子量重量和低多分散性。PAS的硫酸化产生这种独特的肝素模拟物。在此，我们描述新的合成沿着详细的体外和离体作用机制和体内功效研究。拟议的实验将确定抗凝活性的分子和结构基础的二硫酸化PAS（disulPAS），并将测试的假设，区域选择性官能化 disulPAS将：1）在体内有效，活性相当于或优于低分子量的重量肝素（LMWH）;和2）与合成磺达肝素不同，被硫酸鱼精蛋白中和。此外，sulPAS抗凝活性将取决于硫酸根的数量和位置功能化，与肝素诱导的血小板减少症无关。重要的是，大量的初步数据支持拟议的研究，充分表征的材料和严格的建立实验设计，并在必要的跨学科合作和专业知识，地方解决的假设。这一五年建议的具体目标如下。要求1 合成并表征了新的区域选择性二硫酸化PAS。目的2评价体外/离体抗凝活性，并确定二硫酸化PAS的作用机制（MOA）。目标3定义了在啮齿类动物模型中的药物代谢动力学和药效学特征血栓预防和出血风险。