Amso Zaid, Kowalczyk Renata, Watson Maureen, Park Young-Eun, Callon Karen E, Musson David S, Cornish Jillian, Brimble Margaret A
School of Chemical Sciences, The University of Auckland, 23 Symonds St, Auckland 1142, New Zealand.
Org Biomol Chem. 2016 Oct 21;14(39):9225-9238. doi: 10.1039/c6ob01455k. Epub 2016 Aug 4.
Preptin is a 34-residue pancreatic hormone shown to be anabolic to bone in vitro and in vivo. The bone activity of preptin resides within the (1-16) N-terminal fragment. Due to its peptidic nature, the truncated fragment of preptin is enzymatically unstable; however it provides an attractive framework for the creation of stable analogues using various peptidomimetic techniques. An alanine scan of preptin (1-16) was undertaken which showed that substitution of Ser at position 3 or Pro at position 14 did not inhibit the proliferative activity of preptin in primary rat osteoblasts (bone-forming cells). Importantly, Ser-3 to Ala substitution also showed a significant activity on osteoblast differentiation in vitro and increased the formation of mineralised bone matrix. Additional modifications with non-proteinogenic amino acids at position 3 improved the stability in liver microsomes, but diminished the osteoblast proliferative activity. In addition, to provide greater structural diversity, a series of macrocyclic preptin (1-16) analogues was synthesised using head-to-tail and head-to-side chain macrolactamisation as well as ring-closing metathesis. However, a detrimental effect on osteoblast activity was observed upon macrocyclisation.
前ptin是一种由34个氨基酸残基组成的胰腺激素，已证实在体外和体内对骨骼具有合成代谢作用。前ptin的骨活性存在于（1-16）N端片段中。由于其肽的性质，前ptin的截短片段在酶促作用下不稳定；然而，它为使用各种拟肽技术创建稳定类似物提供了一个有吸引力的框架。对前ptin（1-16）进行了丙氨酸扫描，结果表明，第3位的丝氨酸或第14位的脯氨酸被取代并不抑制前ptin在原代大鼠成骨细胞（骨形成细胞）中的增殖活性。重要的是，第3位的丝氨酸被丙氨酸取代在体外对成骨细胞分化也显示出显著活性，并增加了矿化骨基质的形成。在第3位用非蛋白质氨基酸进行额外修饰提高了在肝微粒体中的稳定性，但降低了成骨细胞的增殖活性。此外，为了提供更大的结构多样性，使用头对头和头对侧链大环化以及闭环复分解反应合成了一系列大环前ptin（1-16）类似物。然而，大环化后观察到对成骨细胞活性有不利影响。
