School of Biological Sciences, The University of Auckland, 3a Symonds Street, Auckland Central 1010, New Zealand.
School of Biological Sciences, The University of Auckland, 3a Symonds Street, Auckland Central 1010, New Zealand; The Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, 3a Symonds Street, Auckland Central 1010, New Zealand.
Eur J Med Chem. 2017 Aug 18;136:154-164. doi: 10.1016/j.ejmech.2017.05.008. Epub 2017 May 3.
The 20-residue linear peptide A20FMDV2 has been shown to exhibit high selectivity and affinity for the tumour-related αvβ6 integrin and has potential as a vector for therapeutic drugs. However, it exhibits poor half-life in plasma in part due to its high susceptibility to serum proteases. In this study fourteen A20FMDV2 analogues incorporating non-proteinogenic substitutes of the native Lys16 and Leu13 residues and six A20FMDV2 analogues containing modified N- and C-termini were synthesised to increase the half-life and activity of A20FMDV2. The analogues incorporating modified terminal motifs of A20FMDV2 were found to strongly bind to the αvβ6 integrin and were subsequently functionalized with the diethylenetriaminepentaacetic acid chelating agent to facilitate coupling with radioactive indium-111 for human plasma stability and in vivo biodistribution studies. A20FMDV2 peptide variants incorporating an N-terminal d-Asn and C-terminal d-Thr exhibited improved relative activity in vitro and were less susceptible to plasma degradation.
已显示 20 残基线性肽 A20FMDV2 对肿瘤相关的 αvβ6 整联蛋白表现出高选择性和亲和力，并有作为治疗药物载体的潜力。然而，由于其对血清蛋白酶的高敏感性，它在血浆中的半衰期较短。在这项研究中，合成了 14 种包含天然赖氨酸 16 和亮氨酸 13 残基的非蛋白原取代物的 A20FMDV2 类似物，以及 6 种包含修饰的 N-和 C-末端的 A20FMDV2 类似物，以提高 A20FMDV2 的半衰期和活性。发现包含 A20FMDV2 修饰末端基序的类似物与 αvβ6 整联蛋白强烈结合，随后用二亚乙基三胺五乙酸螯合剂进行功能化，以促进与放射性铟-111 的偶联，用于人体血浆稳定性和体内生物分布研究。在体外，包含 N-端 d-Asn 和 C-端 d-Thr 的 A20FMDV2 肽变体表现出改善的相对活性，并且对血浆降解的敏感性较低。
