Abstract：
A20FMDV2 is a 20-mer peptide that exhibits high selectivity and affinity for the tumour-related αvβ6 integrin that can compete with extracellular ligands for the crucial RGD binding site, playing a role as a promising αvβ6-specific inhibitor for anti-cancer therapies. Unfortunately, the clinical value of A20FMDV2 is limited by its poor half-life in blood caused by rapid renal excretion and its reported high susceptibility to serum proteases. The incorporation of poly (ethylene glycol) chains, coined PEGylation, is a well-established approach to improve the pharmacokinetic properties of drug molecules. Here, we report a systematic study on the incorporation of a varying number of ethylene glycol units (1-20) into the A20FMDV2 peptide to establish the effects of PEGylation size on the peptide stability in both rat serum and human plasma. In addition, the effect of acetyl and propionyl PEGylation handles on peptide stability is also described. Selected peptide analogues were assessed for integrin-αvβ6-targeted binding, showing good specificity and activity in vitro. Stability studies in rat serum established that all of the PEGylated peptides displayed good stability, and an A20FMDV2 peptide containing twenty ethylene glycol units (PEG20) was the most stable. Surprisingly, the stability testing in human plasma identified shorter PEGs (PEG2 and PEG5) as more resistant to degradation than longer PEGs, a trend which was also observed with affinity binding to integrin αvβ6.
摘要：
A20FMDV2是一种20聚体肽，对肿瘤相关的αvβ6整联蛋白具有高选择性和亲和力，可以与细胞外配体竞争关键的RGD结合位点，在抗癌治疗中发挥有前途的αvβ6特异性抑制剂的作用。不幸的是,A20FMDV2的临床价值受到肾脏快速排泄引起的血液半衰期差和据报道对血清蛋白酶高敏感性的限制.聚（乙二醇）链的掺入，铸造聚乙二醇化，是一种完善的方法来改善药物分子的药代动力学特性。这里,我们报道了一项关于在A20FMDV2肽中掺入不同数量的乙二醇单元（1-20）的系统研究，以确定聚乙二醇化大小对大鼠血清和人血浆中肽稳定性的影响。此外,还描述了乙酰基和丙酰基聚乙二醇化处理对肽稳定性的影响。选定的肽类似物被评估整合素-αvβ6-靶向结合，在体外表现出良好的特异性和活性。大鼠血清中的稳定性研究表明，所有的聚乙二醇化肽都显示出良好的稳定性，并且含有二十个乙二醇单元(PEG20)的A20FMDV2肽是最稳定的。令人惊讶的是,在人血浆中的稳定性测试发现，较短的PEGs（PEG2和PEG5）比较长的PEGs更能抵抗降解，也观察到与整联蛋白αvβ6亲和结合的趋势。
