肌肽在糖氧化应激啮齿动物模型中的保护作用为糖尿病肾病患者的治疗概念中这些发现的翻译提供了合理的依据。然而,与啮齿动物相比,肌肽被肌氨酸酶-1酶迅速降解。为了克服这个障碍,我们试图通过与甲氧基聚乙二醇胺(mPEG-NH2)缀合来保护肌肽的水解。PEG化肌肽(PEG-car)用于研究人血清对肌肽的水解,以及比较静脉内(IV)注射后PEG-car和L-肌肽在小鼠中的药代动力学。而L-肌肽在人血清中快速水解,PEG-car对水解具有高度抗性。向肌肽或PEG-car添加未缀合的PEG不影响血清中肌肽的水解。在小鼠中,PEG-car和L-肌肽在血清中表现出相似的药代动力学,但在肾脏中的半衰期(t1/2)不同,PEG-car显示与L-肌肽相比显著更高的t1/2。因此,肌肽的聚乙二醇化是防止肌肽降解和获得更高的肾肌肽水平的有效方法。然而,需要进一步的研究来测试聚乙二醇化后肌肽的保护特性是否得到保留。
Carnosine\'s protective effect in rodent models of glycoxidative stress have provided a rational for translation of these findings in therapeutic concepts in patient with diabetic kidney disease. In contrast to rodents however,
carnosine is rapidly degraded by the carnosinase-1 enzyme. To overcome this hurdle, we sought to protect hydrolysis of carnosine by conjugation to Methoxypolyethylene glycol amine (mPEG-NH2). PEGylated
carnosine (PEG-car) was used to study the hydrolysis of
carnosine by human serum as well as to compare the pharmacokinetics of PEG-car and L-carnosine in mice after intravenous (IV) injection. While L-carnosine was rapidly hydrolyzed in human serum, PEG-car was highly resistant to hydrolysis. Addition of unconjugated PEG to
carnosine or PEG-car did not influence hydrolysis of
carnosine in serum. In mice PEG-car and L-carnosine exhibited similar pharmacokinetics in serum but differed in half-life time (t1/2) in kidney, with PEG-car showing a significantly higher t1/2 compared to L-carnosine. Hence, PEGylation of
carnosine is an effective approach to prevent
carnosine degradations and to achieve higher renal
carnosine levels. However, further studies are warranted to test if the protective properties of carnosine are preserved after PEGylation.