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Total chemical synthesis of a heterodimeric interchain bis-lactam-linked Peptide: application to an analogue of human insulin-like Peptide 3.


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Authors

Karas, John 
Shabanpoor, Fazel 
Hossain, Mohammed Akhter 
Gardiner, James 
Separovic, Frances 

Abstract

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.

Description

Keywords

3405 Organic Chemistry, 34 Chemical Sciences, Generic health relevance

Journal Title

Int J Pept

Conference Name

Journal ISSN

1687-9767
1687-9775

Volume Title

Publisher

Hindawi Limited