The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.
School of Chemistry, University of Melbourne, Melbourne, VIC, 3010, Australia.
Angew Chem Int Ed Engl. 2016 Nov 14;55(47):14552-14556. doi: 10.1002/anie.201604733. Epub 2016 Aug 16.
Heterodimeric peptides linked by disulfide bonds are attractive drug targets. However, their chemical assembly can be tedious, time-consuming, and low yielding. Inspired by the cellular synthesis of pro-insulin in which the two constituent peptide chains are expressed as a single-chain precursor separated by a connecting C-peptide, we have developed a novel chemically cleavable bis-linker tether which allows the convenient assembly of two peptide chains as a single "pro"-peptide on the same solid support. Following the peptide cleavage and post-synthetic modifications, this bis-linker tether can be removed in one-step by chemical means. This method was used to synthesize a drug delivery-cargo conjugate, TAT-PKCi peptide, and a two-disulfide bridged heterodimeric peptide, thionin (7-19)-(24-32R), a thionin analogue. To our knowledge, this is the first report of a one-pot chemically cleavable bis-linker strategy for the facile synthesis of cross-bridged two-chain peptides.
二硫键连接的杂二聚体肽是有吸引力的药物靶点。然而，它们的化学组装可能繁琐、耗时且产率低。受细胞内前胰岛素合成的启发，其中两个组成肽链被表达为通过连接 C 肽分隔的单链前体，我们开发了一种新型的化学可裂解双连接子接头，允许将两条肽链作为单个“前”肽在同一固相载体上方便地组装。在肽切割和合成后修饰之后，可以通过化学手段一步去除该双连接子接头。该方法用于合成药物递送载体缀合物 TAT-PKCi 肽和二硫键桥联的杂二聚体肽 thionin (7-19)-(24-32R)，一种硫堇类似物。据我们所知，这是首次报道一种一锅化学可裂解双连接子策略，用于方便地合成交联双链肽。
