Karas John, Shabanpoor Fazel, Hossain Mohammed Akhter, Gardiner James, Separovic Frances, Wade John D, Scanlon Denis B
Bio21 Institute, University of Melbourne, Melbourne, VIC 3010, Australia ; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC 3010, Australia ; School of Chemistry, University of Melbourne, Melbourne, VIC 3010, Australia ; CSIRO Materials Science & Engineering, Clayton, VIC 3168, Australia.
Int J Pept. 2013;2013:504260. doi: 10.1155/2013/504260. Epub 2013 Oct 28.
Nonreducible cystine isosteres represent important peptide design elements in that they can maintain a near-native tertiary conformation of the peptide while simultaneously extending the in vitro and in vivo half-life of the biomolecule. Examples of these cystine mimics include dicarba, diselenide, thioether, triazole, and lactam bridges. Each has unique physicochemical properties that impact upon the resulting peptide conformation. Each also requires specific conditions for its formation via chemical peptide synthesis protocols. While the preparation of peptides containing two lactam bonds within a peptide is technically possible and reported by others, to date there has been no report of the chemical synthesis of a heterodimeric peptide linked by two lactam bonds. To examine the feasibility of such an assembly, judicious use of a complementary combination of amine and acid protecting groups together with nonfragment-based, total stepwise solid phase peptide synthesis led to the successful preparation of an analogue of the model peptide, insulin-like peptide 3 (INSL3), in which both of the interchain disulfide bonds were replaced with a lactam bond. An analogue containing a single disulfide-substituted interchain lactam bond was also prepared. Both INSL3 analogues retained significant cognate RXFP2 receptor binding affinity.
不可还原的胱氨酸等排体是重要的肽设计元素，因为它们可以维持肽的近天然三级构象，同时延长生物分子在体外和体内的半衰期。这些胱氨酸模拟物的例子包括二碳桥、二硒键、硫醚、三唑和内酰胺桥。每种都具有独特的物理化学性质，会影响所得肽的构象。每种通过化学肽合成方案形成也都需要特定条件。虽然在肽内制备含有两个内酰胺键的肽在技术上是可行的，并且有其他人报道过，但迄今为止，尚未有关于通过两个内酰胺键连接的异二聚体肽的化学合成的报道。为了研究这种组装的可行性，明智地使用胺和酸保护基团的互补组合以及基于非片段的全逐步固相肽合成，成功制备了模型肽胰岛素样肽3（INSL3）的类似物，其中两条链间二硫键均被内酰胺键取代。还制备了含有单个二硫键取代的链间内酰胺键的类似物。两种INSL3类似物均保留了显著的同源RXFP2受体结合亲和力。
