Peptidepeptoids

Peptidepeptoids are a class of hybrid macromolecules that merge features of peptides and peptoids. They combine conventional amino acid residues linked by peptide bonds with N-substituted glycine units (peptoids) within the same polymer backbone, producing a mixed sequence that can leverage the advantages of both chemistries. The concept aims to retain the recognition properties of peptides while improving stability and design flexibility offered by peptoids.

Structurally, peptidepeptoids feature a backbone that includes both amide bonds and N-substituted linkages. Some residues may be ordinary amino acids, while others are peptoid units in which the side chain is attached to the nitrogen of the backbone rather than the alpha carbon. This arrangement allows mixed sequences where the distribution and location of peptide versus peptoid segments influence overall conformation, hydrogen-bonding patterns, and dynamics.

Synthesis and design generally combine methods from peptide and peptoid chemistry. Sequential solid-phase synthesis can be employed, using standard Fmoc-SPPS for peptide segments and the peptoid submonomer approach for N-substituted glycine units, with orthogonal protections to control sequence incorporation. Convergent strategies that assemble modular blocks are also used. The design focuses on tunable ratios of peptide to peptoid content to tailor stability, activity, and physicochemical properties.

Properties and applications are driven by the mixed backbone. The peptoid component often confers proteolytic resistance and altered lipophilicity, while peptide portions retain biological recognition and folding potential. Potential applications include therapeutic agents, enzyme inhibitors, receptor ligands, and materials with programmable assembly. Research is ongoing to establish design rules and to demonstrate robust in vivo function.