Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand; Department of Molecular Medicine and Pathology, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
Chem Biol Drug Des. 2013 Oct;82(4):429-37. doi: 10.1111/cbdd.12168.
Peptide hormones that modulate insulin secretion have been recognized to have therapeutic potential, with peptides such as amylin (pramlintide acetate, Symlin) and exendin-4 (exenatide, Byetta) now commercially available. Preptin is a peptide that has been shown to increase insulin secretion in vitro and in vivo. Here, we describe the first chemical synthesis and analysis of a short series of preptin analogues based on the rat preptin sequence. Phe 21 in the preptin sequence was substituted with the non-protein amino acids D-Phe, D-Hphe, 3-aminobenzoic acid and 1-aminocyclooctane-1-carboxylic acid, which rendered the preptin analogues resistant to chymotryptic protease hydrolysis at this position. Substitution of Phe 21 with these non-protein amino acids did not abrogate the insulin secretory effect of preptin, with analogues showing a similar dose-dependent effect on insulin secretion from βTC6-F7 mouse β-cells in both the presence and absence of glucose as unmodified rat preptin. Further studies on the stability of the preptin analogues and their effect on insulin secretion are in progress.
已经发现调节胰岛素分泌的肽类激素具有治疗潜力，目前已有商业化的肽类药物，如胰淀素（醋酸普兰林肽，Symlin）和 exendin-4（艾塞那肽，Byetta）。Preptin 是一种已被证明可在体外和体内增加胰岛素分泌的肽。在这里，我们描述了基于大鼠 Preptin 序列的一系列短肽类似物的首次化学合成和分析。Preptin 序列中的 Phe21 被非蛋白氨基酸 D-Phe、D-Hphe、3-氨基苯甲酸和 1-氨基环辛烷-1-羧酸取代，这使得 Preptin 类似物在该位置对糜蛋白酶水解具有抗性。用这些非蛋白氨基酸取代 Phe21 并没有使 Preptin 的胰岛素分泌作用丧失，类似物在存在和不存在葡萄糖的情况下，对βTC6-F7 小鼠β细胞的胰岛素分泌均表现出类似的剂量依赖性作用，与未修饰的大鼠 Preptin 相似。正在进行有关 Preptin 类似物稳定性及其对胰岛素分泌影响的进一步研究。
