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International Journal of Peptides
Volume 2013 (2013), Article ID 504260, 8 pages
Research Article

Total Chemical Synthesis of a Heterodimeric Interchain Bis-Lactam-Linked Peptide: Application to an Analogue of Human Insulin-Like Peptide 3

1Bio21 Institute, University of Melbourne, Melbourne, VIC 3010, Australia
2The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC 3010, Australia
3School of Chemistry, University of Melbourne, Melbourne, VIC 3010, Australia
4CSIRO Materials Science & Engineering, Clayton, VIC 3168, Australia
5MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, UK
6The Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC 3010, Australia
7Department of Chemistry, University of Adelaide, Adelaide, SA 5005, Australia

Received 16 April 2013; Revised 31 August 2013; Accepted 2 September 2013

Academic Editor: Jean-Marie Zajac

Copyright © 2013 John Karas et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.