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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.

项目摘要/摘要本提案描述了一种新型生物材料和合成抗凝剂。抗凝血剂是中流砥柱现代外科手术和凝血障碍治疗，如静脉血栓形成，但性能和最广泛使用的药物--肝素存在供应限制。具体地说，肝素的异质性结构提供了高度可变的活性、患者依赖的剂量反应和危及生命的副作用如肝素引起的血小板减少症。此外，非洲猪瘟(一种双链DNA病毒) 在阿法尔病毒科)已经消灭了世界上超过四分之一的生猪种群，导致全球短缺、污染问题以及对替代品的需要--即非动物来源的抗凝血剂。我们建议使用二硫化聚氨基糖(PASS)作为肝素模拟物。通行证是新的井- 已定义的、对映体碳水化合物聚合物，具有立体化学定义、亲水性和脊椎中的吡喃糖环。阴离子开环聚合高效合成PASS β-内酰胺糖单体的高产率反应，批次间一致性，确定的分子重量和低多分散性。PAS的硫酸盐化产生了这种独特的肝素模拟物。在此，我们描述了新的合成方法以及详细的体内外作用机制和体内疗效研究。拟议的实验将确定抗凝血剂活性的分子和结构基础。并将检验区域选择性官能化的假设二硫代PASs将是：1)体内有效，活性相当于或高于低分子重量肝素(LMWH)；和2)与合成的丰达肝素不同，由鱼精蛋白硫酸盐中和。此外，硫酸盐的抗凝血活性将取决于硫酸盐的数量和位置。与肝素引起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，材料特征良好，严谨实验设计已建立，基本的跨学科协作和专业知识在解决这些假设的地方。这一五年计划的具体目标如下。目标1 合成并表征了新的区域选择性二硫化PAS。AIM 2体外/体外评价抗凝血活性，并确定二硫化PASS的作用机制(MOA)。目标3定义了二磺酸铅候选制剂在啮齿动物模型中的药代动力学和药效学研究血栓预防和出血风险。