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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/文摘