Kalaska Bartlomiej, Miklosz Joanna, Kamiński Kamil, Musielak Bogdan, Yusa Shin-Ichi, Pawlak Dariusz, Nowakowska Maria, Szczubiałka Krzysztof, Mogielnicki Andrzej
Department of Pharmacodynamics, Medical University of Bialystok Mickiewicza 2c 15-089 Bialystok Poland
Faculty of Chemistry, Jagiellonian University Gronostajowa 2 30-387 Krakow Poland
RSC Adv. 2019 Jan 23;9(6):3020-3029. doi: 10.1039/c8ra09724k. eCollection 2019 Jan 22.
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 and 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.
除了调节配体-受体和细胞-细胞相互作用外，硫酸乙酰肝素（HS）可能参与许多疾病的发展，如癌症、细菌或病毒感染及其并发症，如出血或炎症。在这些情况下，中和HS可能是一个潜在的治疗靶点。我们之前报道过肝素结合共聚物（HBC，PEG41-PMAPTAC53）是一种用于高效安全中和肝素和合成抗凝剂的全合成化合物。在寻找HS的分子拮抗剂时，我们研究了HBC作为HS抑制剂在体外和体内的活性，并对HBC/HS复合物进行了表征。使用比色天青A法、等温滴定量热法和动态光散射技术，我们发现HBC通过形成小于200 nm的复合物以小于1:1的化学计量比结合HS。我们通过测量活化部分凝血活酶时间、凝血酶原时间、抗Xa因子活性、抗IIa因子活性和血小板聚集，在大鼠中证实了HBC的抑制作用。HBC逆转了由HS引起的所有测试参数的增强，表明阳离子合成嵌段共聚物在涉及HS过度产生的各种疾病中可能具有治疗价值。
