Synthesis of tailored C-glycosyl amino acids reveals distinct effects on peptide conformation, suggesting utility in drug development and catalysis.
C ‐glycosylation is a well‐established strategy for improving the pharmacokinetic properties of peptides; however, the influence of chiral C ‐glycosyl amino acid incorporation on peptide conformation remains insufficiently explored. Most existing synthetic approaches restrict C ‐glycosyl amino acid placement to the N ‐terminus, C ‐terminus, or specific residues containing pre‐installed reactive groups. Here, we present a more versatile strategy based on the design and synthesis of customized C ‐glycosyl amino acids. Four variants bearing protected galactopyranose, ribofuranose, sorbofuranose, or allofuranose side chains were synthesized and incorporated into peptides using a solid‐phase methodology, enabling substitution at diverse sequence positions. Detailed NMR analyses revealed that each C ‐glycosyl α‐amino acid promotes distinct conformational preferences, primarily stabilized by hydrogen‐bonding networks between backbone amides and carbohydrate side chains. These findings uncover conformational information encoded within four non‐canonical C ‐glycosyl α‐amino acids, offering new molecular tools for catalysis, materials development and drug discovery.
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Bogović et al. (2025) studied this question.
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