School of Chemistry , The University of Sydney , Sydney , NSW 2006 , Australia.
School of Life and Environmental Sciences , The University of Sydney , Sydney , NSW 2006 , Australia.
J Am Chem Soc. 2018 Oct 17;140(41):13327-13334. doi: 10.1021/jacs.8b07877. Epub 2018 Oct 8.
Polyproline sequences are highly abundant in prokaryotic and eukaryotic proteins, where they serve as key components of secondary structure. To date, construction of the proline-proline motif has not been possible owing to steric congestion at the ligation junction, together with an n → π* electronic interaction that reduces the reactivity of acylated proline residues at the C-terminus of peptides. Here, we harness the enhanced reactivity of prolyl selenoesters and a trans-γ-selenoproline moiety to access the elusive proline-proline junction for the first time through a diselenide-selenoester ligation-deselenization manifold. The efficient nature of this chemistry is highlighted in the high-yielding one-pot assembly of two proline-rich polypeptide targets, submaxillary gland androgen regulated protein 3B and lumbricin-1. This method provides access to the most challenging of ligation junctions, thus enabling the construction of previously intractable peptide and protein targets of increasing structural complexity.
多聚脯氨酸序列在原核和真核蛋白质中高度丰富，它们作为二级结构的关键组成部分。迄今为止，由于连接点的空间拥挤以及 n → π* 电子相互作用降低了肽 C 末端酰化脯氨酸残基的反应性，因此一直无法构建脯氨酸-脯氨酸基序。在这里，我们利用脯氨酸硒酸酯和反式-γ-硒代脯氨酸部分的增强反应性，首次通过二硒化物-硒酸酯连接-去硒化多面体型来获得难以捉摸的脯氨酸-脯氨酸连接点。这种化学方法的高效性在两种富含脯氨酸的多肽靶标的高产一锅组装中得到了突出体现，即颌下腺雄激素调节蛋白 3B 和蚯蚓素-1。该方法可用于构建最具挑战性的连接点，从而能够构建结构复杂性不断增加的以前难以处理的肽和蛋白质靶标。
