新的凝血酶抑制剂肽紫外线的卵高延长体内循环和增强的抗血栓形成效应
PEGylation of New Thrombin Inhibitor Peptide Ultravariegin for Prolonged In Vivo Circulation and Enhanced Antithrombotic Effects
影响因子:4.50000
分区:医学2区 / 药学2区 医学：研究与实验3区
发表日期:2024 Dec 02
作者:
Xia Song, Yuting Wen, Aaron Wei Liang Li, Jingling Zhu, Cho Yeow Koh, R Manjunatha Kini, Mark Yan Yee Chan, Jun Li
摘要
抗凝治疗通常用于预防和治疗心血管疾病，脑血管疾病和癌症患者的动脉和静脉血凝块。静脉血凝块是急性冠状动脉疾病和中风后心血管死亡的第三大主要原因。非常需要有效的抗凝治疗，而出血风险很小。 Variegin及其变体是一种新型的抗凝结肽，在临床前研究中显示出令人鼓舞的结果。 Variegin及其最佳变体Ultravariegin（UV）可以更有效地抑制血凝块的形成，同时比肝素和Bivalirudin等传统药物降低出血。但是，紫外线的寿命短仍然是其在临床环境中使用的限制。 Pegylation是一种将聚（乙二醇）（PEG）连接到肽或药物的方法，可以通过将其在体内延长其循环时间来帮助提高紫外线的有效性。在这项研究中，使用Malemide-Peg5k和10k将紫外线呈紫外线。在大鼠和兔血浆中评估了卵缘化对紫外线抗凝血酶活性的影响，显示对功效的影响最小。在大鼠和兔子中进行体内研究表明，叶状紫外线的半衰期比未修饰的紫外线更长，抗凝作用更大，尤其是在皮下施用时。 Pegylation显着延长了兔子中紫外线的半衰期，从而导致长达4天的持续抗凝作用。这表明，增加紫外线的尺寸并用钉子屏蔽紫外线可以通过肾脏降低清除率并延长其循环时间。紫外线紫外线的改善的半衰期和抗凝血酶活性使其成为抗凝治疗的更有利选择。
Abstract
Anticoagulant therapy is commonly used to prevent and treat arterial and venous blood clots in patients with cardiovascular disease, cerebrovascular disease, and cancer. Venous blood clots are the third leading cause of cardiovascular death following acute coronary artery disease and stroke. There is a significant need for effective anticoagulant therapy with minimal risk of bleeding. Variegin and its variants are a new type of antithrombin peptide that has shown promising results in preclinical studies. Variegin and its best variant, ultravariegin (UV), can more effectively inhibit blood clot formation while causing less bleeding than traditional medications such as heparin and bivalirudin. However, the short lifespan of UV remains a limitation for its use in clinical settings. PEGylation, a method of conjugating poly(ethylene glycol) (PEG) chains to peptides or drugs, may help improve the effectiveness of UV by extending its circulation time in the body. In this study, UV was PEGylated using maleimide-PEG5k and 10k. The impact of PEGylation on the antithrombin activity of UV was assessed in vitro and ex vivo in rat and rabbit plasma, showing minimal effects on the efficacy. In vivo studies in rats and rabbits revealed that PEGylated UV had a longer half-life and greater anticoagulant effects than unmodified UV did, especially when it was administered subcutaneously. PEGylation significantly extended the half-life of UV in rabbits, resulting in sustained anticoagulant effects for up to 4 days. This demonstrated that increasing the size of UV and shielding it with PEG could reduce clearance by the kidneys and prolong its circulation time. The improved half-life and antithrombin activity of PEGylated UV make it a more favorable choice for anticoagulant therapy.