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.

Highlights

  • Cysteine-rich peptides such as conotoxins and insulin-like peptides are an increasingly important class of biomolecules

  • insulin-like peptide 3 (INSL3) was chosen as the model system to evaluate lactam bonds as cystine isosteres in complex peptide structures

  • Bullesbach and Schwabe prepared analogues of human INSL3 in which one or the other of the two interchain disulfide bonds were replaced with a lactam bond, in which the purpose was to study the role of the native cystine (A11-B10) and (A24B22) bonds in both binding and receptor activation [29]

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Summary

Introduction

Cysteine-rich peptides such as conotoxins and insulin-like peptides are an increasingly important class of biomolecules. INSL3 was chosen as the model system to evaluate lactam bonds as cystine isosteres in complex peptide structures. Bullesbach and Schwabe prepared analogues of human INSL3 in which one or the other of the two interchain disulfide bonds were replaced with a lactam bond, in which the purpose was to study the role of the native cystine (A11-B10) and (A24B22) bonds in both binding and receptor activation [29].

Results
Conclusion

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