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Collagen, the major structural protein in connective tissue, adopts a right‐handed triple helix composed of peptide chains featuring repeating Gly‐Xaa‐Yaa tripeptide motifs. While the cyclic residues proline (Pro) and hydroxyproline (Hyp) are prevalent in the Xaa and Yaa positions due to their PPII‐favoring conformational properties, diverse acyclic peptoid (N‐alkylated Gly) residues can also stabilize the collagen fold. Here, we investigated the effects of N‐aminoglycine (aGly) derivatives—so‐called “azapeptoid” residues—on the thermal stability of collagen mimetic peptides (CMPs). Substitution of Pro at the central Xaa11 position with aGly resulted in destabilization of the triple helix, yet the introduction of select N′‐alkyl groups (isopropyl, butyl) partially restored thermal stability. Moreover, the N‐amino group of azapeptoid residues enhanced thermal CMP stability relative to an unsubstituted Gly analog. Kinetic studies revealed that the introduction of the hydrazide bonds in aGly and (iPr)aGly CMPs did not significantly impact triple helix refolding rates. Their modular late‐stage derivatization and tunable properties highlight azapeptoid residues as potentially valuable tools for engineering CMPs and probing the structural determinants of collagen folding. 

The chemical modification of peptides is a promising approach for the design of protein-protein interaction inhibitors and peptide-based drug candidates. Among several peptidomimetic strategies, substitution of the amide backbone maintains side-chain functionality that may be important for engagement of biological targets. Backbone amide substitution has been largely limited to N-alkylation, which can promote cis amide geometry and disrupt important H-bonding interactions. In contrast, N-amination of peptides induces distinct backbone geometries and maintains H-bond donor capacity. In this chapter we discuss the conformational characteristics of designed N-amino peptides and present a detailed protocol for their synthesis on solid support. The described methods allow for backbone N-amino scanning of biologically active parent sequences.