Werle M, Bernkop-Schnürch A
ThioMatrix GmbH, Research Center Innsbruck, Innsbruck, Austria.
Amino Acids. 2006 Jun;30(4):351-67. doi: 10.1007/s00726-005-0289-3. Epub 2006 Apr 20.
Due to the obvious advantages of long-acting peptide and protein drugs, strategies to prolong plasma half life time of such compounds are highly on demand. Short plasma half life times are commonly due to fast renal clearance as well as to enzymatic degradation occurring during systemic circulation. Modifications of the peptide/protein can lead to prolonged plasma half life times. By shortening the overall amino acid amount of somatostatin and replacing L: -analogue amino acids with D: -amino acids, plasma half life time of the derivate octreotide was 1.5 hours in comparison to only few minutes of somatostatin. A PEG(2,40 K) conjugate of INF-alpha-2b exhibited a 330-fold prolonged plasma half life time compared to the native protein. It was the aim of this review to provide an overview of possible strategies to prolong plasma half life time such as modification of N- and C-terminus or PEGylation as well as methods to evaluate the effectiveness of drug modifications. Furthermore, fundamental data about most important proteolytic enzymes of human blood, liver and kidney as well as their cleavage specificity and inhibitors for them are provided in order to predict enzymatic cleavage of peptide and protein drugs during systemic circulation.
由于长效肽和蛋白质药物具有明显优势，延长此类化合物血浆半衰期的策略需求很高。血浆半衰期短通常是由于肾脏快速清除以及全身循环过程中发生的酶降解。肽/蛋白质的修饰可导致血浆半衰期延长。通过缩短生长抑素的总氨基酸量并用D-氨基酸替代L-类似物氨基酸，衍生物奥曲肽的血浆半衰期为1.5小时，而生长抑素仅为几分钟。与天然蛋白相比，聚乙二醇（2,40K）缀合的干扰素α-2b的血浆半衰期延长了330倍。本综述的目的是概述延长血浆半衰期的可能策略，如N端和C端修饰或聚乙二醇化以及评估药物修饰效果的方法。此外，还提供了有关人体血液、肝脏和肾脏中最重要的蛋白水解酶及其切割特异性和抑制剂的基础数据，以便预测肽和蛋白质药物在全身循环过程中的酶促切割。
