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The neutralization of heparan sulfate by heparin-binding copolymer as a potential therapeutic target

机译：肝素结合共聚物中和硫酸肝素作为潜在的治疗靶标

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Besides regulating ligand–receptor and cell–cell interactions, heparan sulfate (HS) may participate in the development of many diseases, such as cancer, bacterial or viral infections, and their complications, like bleeding or inflammation. In these cases, the neutralization of HS could be a potential therapeutic target. The heparin-binding copolymer (HBC, PEG41-PMAPTAC53) was previously reported by us as a fully synthetic compound for efficient and safe neutralization of heparins and synthetic anticoagulants. In a search for molecular antagonists of HS, we examined the activity of HBC as an HS inhibitor both in vitro and in vivo and characterized HBC/HS complexes. Using a colorimetric Azure A method, isothermal titration calorimetry and dynamic light scattering techniques we found that HBC binds HS by forming complexes below 200 nm with less than 1?:?1 stoichiometry. We confirmed the HBC inhibitory effect in rats by measuring activated partial thromboplastin time, prothrombin time, anti-factor Xa activity, anti-factor IIa activity, and platelet aggregation. HBC reversed the enhancement of all tested parameters caused by HS demonstrating that cationic synthetic block copolymers may have a therapeutic value in various disorders involving overproduction of HS.
机译：除了调节配体-受体和细胞-细胞的相互作用，硫酸乙酰肝素（HS）可能参与许多疾病的发展，例如癌症，细菌或病毒感染及其并发症，例如出血或炎症。在这些情况下，HS的中和可能是潜在的治疗目标。肝素结合共聚物（HBC，PEG41-PMAPTAC53）先前已被我们报道为完全合成的化合物，可有效，安全地中和肝素和合成抗凝剂。在寻找HS的分子拮抗剂时，我们在体外和体内检查了HBC作为HS抑制剂的活性，并鉴定了HBC / HS复合物。使用比色Azure A方法，等温滴定热法和动态光散射技术，我们发现HBC通过形成低于200 nm，化学计量小于1？：？1的复合物来结合HS。我们通过测量活化的部分凝血活酶时间，凝血酶原时间，抗因子Xa活性，抗因子IIa活性和血小板凝集，证实了HBC在大鼠中的抑制作用。 HBC逆转了由HS引起的所有测试参数的提高，表明阳离子合成嵌段共聚物可能在涉及HS过度生产的各种疾病中具有治疗价值。

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