The School of Chemical Sciences, University of Auckland, 23 Symonds St, Auckland 1010, New Zealand.
Centre for Tumour Biology, Barts Cancer Institute-Cancer Research UK Centre of Excellence, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
Molecules. 2022 Jul 6;27(14):4331. doi: 10.3390/molecules27144331.
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 (PEG) was the most stable. Surprisingly, the stability testing in human plasma identified shorter PEGs (PEG and PEG) as more resistant to degradation than longer PEGs, a trend which was also observed with affinity binding to integrin αvβ6.
A20FMDV2 是一种 20 肽，对肿瘤相关的 αvβ6 整联蛋白具有高选择性和亲和力，可与细胞外配体竞争关键的 RGD 结合位点，作为一种有前途的 αvβ6 特异性抑制剂用于癌症治疗。不幸的是，A20FMDV2 的临床价值受到其在血液中半衰期短的限制，这是由于其快速的肾脏排泄引起的，并且据报道其对血清蛋白酶的敏感性很高。聚乙二醇（PEG）链的掺入，即 PEGylation，是一种改善药物分子药代动力学性质的成熟方法。在这里，我们报告了一项关于将不同数量的乙二醇单元（1-20）掺入 A20FMDV2 肽中的系统研究，以确定 PEGylation 大小对肽在大鼠血清和人血浆中的稳定性的影响。此外，还描述了乙酰基和丙酰基 PEG 化处理对肽稳定性的影响。评估了选定的肽类似物对整联蛋白-αvβ6 靶向结合的作用，体外显示出良好的特异性和活性。在大鼠血清中的稳定性研究表明，所有 PEG 化肽都显示出良好的稳定性，并且含有二十个乙二醇单元（PEG）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表明，较短的 PEG（PEG 和 PEG）比较长的 PEG 更能抵抗降解，这种趋势在与整联蛋白 αvβ6 的亲和力结合中也观察到。
