Solid-Phase Synthetic Approaches to C-Terminal and Backbone-Modified Peptide Analogues for Drug Discovery

Introduction:
The development of efficient strategies for C-terminal peptide modification and amide bond replacement is an important approach toward the synthesis of peptide analogues with improved physicochemical and biological properties. Herein, we present a series of solid-phase synthetic methodologies for the preparation of C-terminally modified peptides and peptide bond isosteres.

Methods:
Solid-phase peptide synthesis (SPPS) protocols employing resin-bound mercapto acids and aminothiols were developed for the preparation of C-terminal mercapto acid- and aminothiol-containing peptides. In addition, methodologies were established for the synthesis of C-terminal 2-benzothiazolyl peptide derivatives. Backbone modification was achieved through replacement of the amide bond with either a thioether linkage (CH₂–S) or an aminomethylene linkage (CH₂–NH). These transformations were accomplished using on-resin nucleophilic addition and reductive amination reactions, respectively.

Results:
The proposed strategies afforded a diverse range of modified peptide analogues in high yields and excellent purity. The methodologies demonstrated broad applicability, enabling the incorporation of multiple C-terminal functionalities and amide bond replacements. Furthermore, the synthetic intermediates were readily accessible and suitable for further structural diversification, highlighting the versatility and scalability of the developed approaches.

Conclusions:
The described methodologies provide efficient and versatile routes to C-terminally modified peptides and peptide bond isosteres. Their high yields, purity, scalability, and readily available intermediates make them valuable tools for peptide-based drug discovery. The diversity of accessible peptide structures offers a robust platform for future applications in medicinal chemistry, chemical biology, and collaborative studies directed toward the development of novel bioactive peptide analogues.