In vitro and in vivo safety studies indicate that R15, a synthetic polyarginine peptide, could safely reverse the effects of unfractionated heparin,FEBS Open Bio

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In vitro and in vivo safety studies indicate that R15, a synthetic polyarginine peptide, could safely reverse the effects of unfractionated heparin
FEBS Open Bio ( IF 2.8 ) Pub Date : 2021-06-29 , DOI: 10.1002/2211-5463.13240
Tong Li ₁ , Zhiyun Meng ₁ , Xiaoxia Zhu ₁ , Hui Gan ₁ , Ruolan Gu ₁ , Zhuona Wu ₁ , Taoyun Liu ₁ , Peng Han ₁ , Jiarui Gao ₁ , Su Han ₁ , Guifang Dou ₁

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Unfractionated heparin (UFH) is an anionic glycosaminoglycan that is widely used to prevent blood clotting. However, in certain cases, unwanted side effects can require it to be neutralized. Protamine sulfate (PS), a basic peptide rich in arginine, is the only approved antagonist for UFH neutralization. Many adverse reactions occur with the clinical application of PS, including systemic hypotension, pulmonary hypertension, and anaphylaxis. We previously described R15, a linear peptide composed of 15 arginine molecules, as a potential UFH antagonist. In this study, the in-depth safety of R15 was explored to reveal its merits and associated risks in comparison with PS. In vitro safety studies investigated the interactions of R15 with erythrocytes, fibrin, complement, and rat plasma. In vivo safety studies explored potential toxicity and immunogenicity of R15 and the UFH–R15 complex. Results showed that both PS and R15 can induce erythrocyte aggregation, thicken fibrin fibers, activate complement, and cause anticoagulation in a concentration-dependent manner. However, those influences weakened in whole blood or in live animals and were avoided when R15 was in a complex with UFH. We found dramatically enhanced complement activation when there was excess UFH in analyses involving UFH–PS complexes, and a slight increase in those involving UFH–R15 complexes. Within 2 h, R15 was degraded in rat plasma in vitro, whereas PS was not. Enhanced creatinine was found after a single intravenous injection of PS or R15 (900 U·kg⁻¹, body weight), suggesting possible abnormal renal function. The UFH–PS complex, but not the UFH–R15 complex, exhibited obvious immunogenicity. In conclusion, R15 is nonimmunogenic and potentially safe at a therapeutic dose to reverse the effects of UFH.

中文翻译：

体外和体内安全性研究表明，合成聚精氨酸肽 R15 可以安全地逆转普通肝素的作用

普通肝素 (UFH) 是一种阴离子糖胺聚糖，广泛用于预防血液凝固。然而，在某些情况下，不需要的副作用可能需要中和它。硫酸鱼精蛋白 (PS) 是一种富含精氨酸的碱性肽，是唯一被批准用于中和 UFH 的拮抗剂。临床应用PS会出现许多不良反应，包括全身性低血压、肺动脉高压和过敏反应。我们之前描述了 R15，一种由 15 个精氨酸分子组成的线性肽，作为潜在的 UFH 拮抗剂。在这项研究中，探索了 R15 的深度安全性，以揭示其与 PS 相比的优点和相关风险。体外安全性研究调查了 R15 与红细胞、纤维蛋白、补体和大鼠血浆的相互作用。体内安全性研究探索了 R15 和 UFH-R15 复合物的潜在毒性和免疫原性。结果表明，PS和R15均能以浓度依赖性方式诱导红细胞聚集、增厚纤维蛋白纤维、激活补体并引起抗凝作用。然而，这些影响在全血或活体动物中减弱，当 R15 与 UFH 形成复合物时，这些影响就被避免了。我们发现，当涉及 UFH-PS 复合物的分析中存在过量的 UFH 时，补体活化显着增强，而涉及 UFH-R15 复合物的分析则略有增加。在 2 小时内，R15在体外大鼠血浆中被降解，而 PS 没有。单次静脉注射 PS 或 R15 (900 U·kg ^-1，体重），表明可能存在肾功能异常。UFH-PS 复合物而非 UFH-R15 复合物表现出明显的免疫原性。总之，R15 是非免疫原性的，并且在治疗剂量下可能是安全的，可以逆转 UFH 的影响。

更新日期：2021-09-01

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