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/摘要该建议描述了一种新型的生物材料和合成抗凝剂。抗凝剂是主要的支柱现代手术和服装障碍管理（例如静脉血栓形成，虽然表现）和使用最广泛的代理 - 肝素存在供应限制。具体来说，肝素的异质结构可提供高度可变的活动，依赖于患者的剂量回答和威胁生命的副作用例如肝素诱导血小板减少症。此外，非洲猪发烧（双链DNA病毒）在Asfarviridae家族中）已经消除了世界四分之一的猪人口，导致全球短缺，污染问题以及对替代方案的需求 - 即非动物起源的抗凝剂。我们建议将二硫化聚氨基糖（PASS）用作肝素模拟物。通行证是新的定义的，鉴赏碳氢化物聚合物，其立体定义，亲水性并且具有吡喃糖环在骨干中。通过阴离子环聚合有效合成通行证二酰胺糖单体在高产批处理一致性中的反应，定义的分子权重和低分散性。 PA的硫酸化产生了如此独特的肝素模仿。在此，我们描述新型的合成以及详细的体外和实体作用机理以及体内效率研究。提出的实验将定义抗凝活性的分子和结构基础二硫键（Disulpas），将测试调节功能化的假设杜杜通道将是：1）在体内有效的活性等效于或优于低分子重量肝素（LMWH）； 2）与合成酪蛋白瓜不同，被硫酸蛋白硫酸盐中和。此外，硫磺抗凝活性将取决于硫酸盐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，特征良好的材料和严格的材料建立了实验设计，并具有重要的跨学科合作和专业知识解决这些假设的地方。该五年提案的具体目的如下。目标1 合成和字符的新调节的二硫键。 AIM 2评估体外/Ex Vivo 抗凝活性并确定二硫通道的作用机理（MOA）。 AIM 3定义铅二硫代二硫二硫代的药代动力学和药效学特征以及啮齿动物模型中的效率血栓预防和出血风险。